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Each organ/tissue responds to injury and maintains the tissue homeostasis by quickly repairing damaged cells. This method of maintaining the cell mass by controlled proliferation is called regeneration. Degree of regeneration depends on the intensity of the injury. Regeneration capacity also varies with species and tissue type (Table No.1).
Regeneration became a focus of systematic scientific investigation in the 18th century. Abraham Trembly performed detailed experiments on the regeneration of hydra that made a deep impression on the biologists of the time, while Reaumer and Spallanzani reported their observations on the regeneration of limbs in crustaceans and newts, respectively. In 19th century, there were numerous medical and surgical advances that improved the prospects of recovery from serious injury and disease. The development of ether anesthesia made pain-free surgery possible and thus increased the types of wounds that could be made in the human body for the purpose of surgical treatment. Surgery, however, also increased the possibility of death by systemic bacterial infection. Skin grafting, described by Sushruta many centuries earlier, was revived by 19th century surgeons. By far the most fundamental and significant development of the 19th century for biology and medicine was the invention of the tools to understand the biology of individual cell. This was powered by the formulation of the cell theory by Schleiden and Schwann in 1838-1839 and the later microscopic observations of Virchow, Remak and others, which led to the idea that cells are the fundamental units that carry out the chemical reactions of life and that new cells are created by the division of existing cells.
Studies on limb development and regeneration in the latter part of the 19th and the early part of the 20th centuries made major contributions to the understanding of development. Prior to the 20th century, regeneration had been explained by the growth of preformed copies of tissues and appendages residing within the originals, driven by vital forces. Now regeneration was recognized as a regulative process evoked in the remaining part that restored the whole.
Technology application for the regeneration of organ is still under development stage, in medicine clinicians adapted the techniques like the Indian physician, Sushruta, the main technique familiarly know as organ transplantation. ( Stocum et al 2004)
Organ transplantation: Successful human transplants have a relatively long history. The Indian surgeon Sushruta in the second century BC, used autografted skin transplantation in nose reconstruction rhinoplasty. Later, the Italian surgeon Gasparo Tagliacozzi performed successful skin autografts; he also failed consistently with allografts, offering the first suggestion of rejection centuries before that mechanism could possibly be understood. He attributed it to the "force and power of individuality" in his 1596 work De Curtorum Chirurgia per Insitionem. Cosmas and Damian miraculously transplat the (black) leg of the Ethiopian onto the (white) body of Justinian. Ditzingen, 16th century.The first successful corneal allograft transplant was performed in 1837 in a gazelle model; the first successful human corneal transplant, a keratoplastic operation, was performed by Eduard Zirm in Austria in 1905. Pioneering work in the surgical technique of transplantation was made in the early 1900s by the French surgeon Alexis Carrel, with Charles Guthrie, with the transplantation of arteries or veins. Their skillful anastomosis operations, the new suturing techniques, laid the groundwork for later transplant surgery and won Carrel the 1912 Nobel Prize in Physiology or Medicine. From 1902 Carrel performed transplant experiments on dogs. Surgically successful in moving kidneys, hearts and spleens, he was one of the first to identify the problem of rejection, which remained insurmountable for decades.
The first attempted human diseased-donor transplant was performed by the Ukrainian surgeon Yu Yu Voronoy in the 1930s; rejection resulted in failure. Joseph Murray performed the first successful transplant, a kidney transplant between identical twins, in 1954, successful because no immunosuppression was necessary in genetically identical twins. 1951 Medawar suggested that immunosuppressive drugs (cyclosporine, Azathioprine) could be used. Many other new drugs are under development for transplantation. In World War-I, Harold Gillies at Aldershot used the tubed pedicle graft, maintaining a flesh connection from the donor site until the graft established its own blood flow. Gillies' assistant, Archibald McIndoe, carried on the work into World War-II as reconstructive surgery. In 1962 the first successful replantation surgery was performed - re-attaching a severed limb and restoring (limited) function and feeling. Transplant of a single gonad (testis) from a living donor was carried out in early July 1926 in Zajecar, Serbia, by a Russian emigré surgeon Dr. Peter Vasil'evic Kolesnikov. (v. Timocki medicinski glasnik, Vol.29 (2004) #2, p.115-117 ISSN 0350-2899 article in Serbian).
Dr. Murray's success with the kidney led to attempts with other organs. There was a successful deceased-donor lung transplant into a lung cancer sufferer in June 1963 by James Hardy in Jackson, Mississippi. The patient survived for eighteen days before dying of kidney failure. Thomas Starzl of Denver attempted a liver transplant in the same year, but was not successful until 1967.
Lung pioneer James Hardy attempted a human heart transplant in 1964, but a premature failure of the recipient's heart caught Hardy with no human donor, he used a chimpanzee heart which failed very quickly. The first success was achieved December 3, 1967 by Christiaan Barnard in Cape Town, South Africa. Louis Washkansky, the recipient, survived for eighteen days amid what many saw as a distasteful publicity circus. The media interest prompted a spate of heart transplants. Over a hundred were performed in 1968-69, but almost all the patients died within sixty days. Barnard's second patient, Philip Blaiberg, lived for 19 months.
As the rising success rate of transplants and modern immunosuppression made transplants more common, the need for more organs has become critical. Advances in living-related donor transplants have made that increasingly common. Additionally, there is substantive research into xenotransplantation or transgenic organs; although these forms of transplant are not yet being used in humans, clinical trials involving the use of specific cell types have been conducted with promising results, such as using porcine islets of Langerhans to treat type one diabetes.However, there are still many problems that would need to be solved before they would be feasible options in patients requiring transplants (Table No.2).
Types of transplants
Autograft: Transplant of tissue to the same person. Sometimes this is done with surplus tissue, or tissue that can regenerate, or tissues more desperately needed elsewhere (examples include skin grafts, vein extraction for CABG, etc.)
Allograft: An allograft is a transplanted organ or tissue from a genetically non-identical member of the same species. Most human tissue and organ transplants are allografts.
Recipient needs immunosuppressive drugs to prevent transplant rejection, destroying the new organ. This dramatically affects the entire immune system making the body vulnerable to pathogens.
Isograft: A subset of allografts in which organs or tissues are transplanted from a donor to a genetically identical recipient (such as an identical twin).
Isografts are differentiated from other types of transplants because while they are anatomically identical to allografts, the same autografts in terms of the recipient's immune response.
Xenograft and Xenotransplantation: A transplant of organs or tissue from one species to another. Examples include porcine heart valve transplants, which are quite common and successful.
Xenotransplantion is often an extremely dangerous type of transplant. For example a baboon-to-human heart transplant failed. Other xenotransplants attempted include piscine-primate (fish to non-human primate) islet (i.e. pancreatic or insular tissue) transplant. The latter research study was intended to pave the way for potential human use if successful.
Split transplants: Sometimes, a deceased-donor organ (specifically the liver) may be divided between two recipients, especially an adult and a child. This is not usually a preferred option, because the transplantation of a whole organ is more successful.
Domino transplants: The success of solid organ transplantation is limited by ongoing problems with organ availability. The uses of extended cadaveric donors as well as the use of living donors are both strategies used to overcome this shortage. One group of potential donors that has not been previously reported are those who have previously received an organ transplant. This type of transplant was first described as a domino transplantation of heart-lung and heart. A combined heart-lung transplant was performed in a patient with end-stage lung disease, but who still had adequate heart performance. The normal heart of this heart-lung recipient was then transplanted into a second patient with end-stage heart disease. In similar types of procedures, the successful retransplantation of a liver allograft from a liver recipient who suffered brain death has been described, as well as retransplantation of a renal allograft. The transplantation of kidneys from a heart transplant recipient who suffered brain death has also been reported (Lowell 2000).
Limitations of organ transplantations:
Technically Organ transplantation has become more routine with success rate >90% in best centres. But, despite the improvement in the surgical techniques, newer immunosuppressive regimes still major setback to organ transplantation program is the donor organ.
Organ demand donors and recipient in the more than 61,000 Americans await body parts demand have in that only about 20,000 transplants are perforemed each year because the demand for human organs far outweighs the supply. In USA,Once for patients with blood type O, who represents 47% of the nation's Liver transplant candidates, the median waiting period in New York City is 511 days while in nearby Northern New Jersey it is only 56 days.
Scientists and clinicians both are trying to over come of the problems with one of the alternative technologies, Stem cells therapy with or without biomaterials, to regenerate damaged tissue and to cure genetically disorders
Milestones in stem cell research:
- 1878-The first attempts were made to fertilize mammalian eggs outside the body.
- 1908 - The term "stem cell" was proposed for scientific use by the Russian histologist Alexander Maksimov (1874-1928) at congress of hematologic society in Berlin. It postulated existence of haematopoietic stem cells.
- 1959-First animals made by in-vitro fertilization (IVF).
- 1960s-Teratocarcinomas determined to originate from embryonic germ cells in mice. Embryonal carcoinoma cells (EC) identified as a kind of stem cell.
- 1960s - Joseph Altman and Gopal Das present scientific evidence of adult neurogenesis, ongoing stem cell activity in the brain; their reports contradict Cajal's "no new neurons" dogma and are largely ignored.
- 1963 - McCulloch and Till illustrate the presence of self-renewing cells in mouse bone marrow.
- 1968-The first human egg is fertilized in vitro.
- 1968 - Bone marrow transplant between two siblings successfully treats SCID.
- 1970s- EC cells injected into mouse blastocysts make chimeric mice. Cultured SC cells are explored as models of embryonic development in mice.
- 1978 - Haematopoietic stem cells are discovered in human cord blood.
- 1978-the first IVF baby is born in England
- 1981 - Mouse embryonic stem cells are derived from the inner cell mass by scientists Martin Evans, Matthew Kaufman, and Gail R. Martin. Gail Martin is attributed for coining the term "Embryonic Stem Cell".
- 1992 - Neural stem cells are cultured in vitro as neurospheres.
- 1997 - Leukemia is shown to originate from a haematopoietic stem cell, the first direct evidence for cancer stem cells.
- 1998 - James Thomson and coworkers derive the first human embryonic stem cell line at the University of Wisconsin-Madison.
- 1984-88-Pluripotent, clonal cells called embryonal carcinoma (EC) cells are developed. When exposed to retinoic acid these cells differentiate into neuron-like cells and other cell types.
- 2000s - Several reports of adult stem cell plasticity are published.
- 2001 - Scientists at Advanced Cell Technology clone first early (four- to six-cell stage) human embryos for the purpose of generating embryonic stem cells.
- 2003 - Dr. Songtao Shi of NIH discovers new source of adult stem cells in children's primary teeth.
- 2004-2005 - Korean researcher Hwang Woo-Suk claims to have created several human embryonic stem cell lines from unfertilised human oocytes. The lines were later shown to be fabricated.
- 2005 - Researchers at Kingston University in England claim to have discovered a third category of stem cell, dubbed cord-blood-derived embryonic-like stem cells (CBEs), derived from umbilical cord blood. The group claims these cells are able to differentiate into more types of tissue than adult stem cells.
- August 2006 - Rat Induced pluripotent stem cells: the journal Cell publishes Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors".
- October 2006 - Scientists at Newcastle University in England create the first ever artificial liver cells using umbilical cord blood stem cells.
- January 2007 - Scientists at Wake Forest University led by Dr. Anthony Atala and Harvard University report discovery of a new type of stem cell in amniotic fluid. This may potentially provide an alternative to embryonic stem cells for use in research and therapy.
- June 2007 - Research reported by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice. In the same month, scientist Shoukhrat Mitalipov reports the first successful creation of a primate stem cell line through somatic cell nuclear transfer
- October 2007 - Mario Capecchi, Martin Evans, and Oliver Smithies win the 2007 Nobel Prize for Physiology or Medicine for their work on embryonic stem cells from mice using gene targeting strategies producing genetically engineered mice (known as knockout mice) for gene research.
- November 2007 - Human Induced pluripotent stem cells: Two similar papers released by their respective journals prior to formal publication: in Cell by Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors", and in Science by Junying Yu, et al., from the research group of James Thomson, "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells": pluripotent stem cells generated from mature human fibroblasts. It is possible now to produce a stem cell from almost any other human cell instead of using embryos as needed previously, albeit the risk of tumorigenesis due to c-myc and retroviral gene transfer remains to be determined.
- January 2008 - Robert Lanza and colleagues at Advanced Cell Technology and UCSF create the first human embryonic stem cells without destruction of the embryo.
- January 2008 - Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts.
- February 2008 - Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach: these iPS cells seem to be more similar to embryonic stem cells than the previous developed iPS cells and not tumorigenic, moreover genes that are required for iPS cells do not need to be inserted into specific sites, which encourage the development of non-viral reprogramming techniques.
- March 2008-The first published study of successful cartilage regeneration in the human knee using autologous adult mesenchymal stem cells is published by Clinicians from Regenerative Sciences.
- October 2008 - Sabine Conrad and colleagues at Tübingen, Germany generate pluripotent stem cells from spermatogonial cells of adult human testis by culturing the cells in vitro under leukemia inhibitory factor (LIF) supplementation.
- 30 October 2008 - Embryonic-like stem cells from a single human hair.
In the last decade, it has observed great impact of regeneration biology in the clinical application.
Presently, scientific community is more concentrating on;
- Understanding the basic biology of the regenerative medicine.
- The cells involved in the regeneration process in each organ.
- Identifying right source of cells (Autologous/allogenic) for therapeutic application.
Stem cell's Immunity:
Embryonic stem cells and factors of rejection
The ES cell transplantation can directly modulate the immune response. Wesselschmidt and McDonald observed that a 50% reduction in the number of macrophages responding to ES cell transplantation compared with Sham-transplanted animals (Rao 2006). Human ES cells have the potential to be rejected following post-transplantion due to the fact that they express low levels of major histocompatibility complex (MHC) class I antigen which can increase after differentiation both in vitro and in vivo. In addition, interferon gamma treatment has been shown to markedly increase MHC class I expression. Recently, it has also been shown that expression of MHC class I on human ES cells is sufficient for rejection by cytotoxic T cells (Drukker et al. 2006). On the other hand, the absence of MHC class II molecules and low-level expression of MHC class I may also lead to natural killer cell rejection of the transplanted cells (Drukker et al. 2002); however, several studies have reported that this is not always the case. Due to a 100-fold increase in the incidence malignant tumours (Penn 2000; Buell et al. 2006) may reduce the quality of life for the patients. Gene modifications to the graft, is worth considering that in addition to direct allo-recognition, the absence of MHC molecules may lead to indirect allo-recognition-mediated rejection and/or natural killer cell-mediated cell destruction (McNerney et al. 2006). The generation of an ES stem cell bank containing HLA-isotype and/or genetically modified human ES cell lines where known HLA backgrounds could be established. But this would involve a massive amount of work to attain pure populations of HLA-defined ES cells, which ultimately may be unachievable.
Adult stem cells in clinical application
MSCs in transplantation
Unlike ES cells donor MSCs have profound immunomodulatory function, both in vivo and in vitro, suggesting that the clinical application of MSCs for tissue regeneration could be achieved. As evidenced by both experimental and clinical data, MSCs have unique immunological characteristics that allow their persistence in an allogeneic environment. In vivo non-human primate studies have elegantly demonstrated that neither allogeneic nor autologous MSCs are rejected but are engrafted into multiple tissues when transplanted in baboons. Clinical studies have demonstrated that MSCs expanded ex vivo can either engraft into tissues or be infused into patients without being rejected, the best examples of which are bone marrow transplantations for the treatment of leukaemia after myeloablative therapies. In vitro studies have indicated that MSCs can directly suppress T cell immune responses, as well as modulate the immune response indirectly through effects on professional antigen presenting cells such as dendritic cells and B cells. MSCs become immunogenic following in vivo differentiation. Other studies have demonstrated that although differentiated or undifferentiated MSCs remain non-immunogenic in vitro, they cannot impart their immunomodulatory activities when cotransplanted to protect allogeneic allografts. One such example was demonstrated by Liu et al. 2006 where they showed that osteogenic differentiated MSCs displayed normal immunosuppressive activities in vitro and in vivo, but their immunomodulatory activity in protecting allogeneic skin allografts was lost following transplantation. The actual mechanisms involved in 'switching off' the non-immunogenic status of MSCs in vivo need to be determined ( Batten et al. 2007).
Neural stem cell in transplantation
In terms of neural grafting, there are several factors that contribute to the timing and intensity of the rejection response and this includes the type of graft transplanted, the degree of immunological disparity between donor and recipient, and how and where the tissue is implanted. (Barker et al. 2004) Although the question is whether neurons or nervous system cells derived from ES cells behave similar or differently from embryonic, fetal and adult stem cells, although this question remains largely unanswered, a growing body of work is beginning to suggest functional difference. The privileged status of the brain is now regarded as the result of a balance of regulated events that produces either immune privilege or effective responses (Widner et al. 1988, Hickey 2001).
The immunology of grafted stem cells has not been extensively studied in depth, when grafting tissue of different immunological disparity, there is local cytokine production that may affect the stability and development of stem cells. The effects of hibernation on the antigenicity of the tissue are not known, although short-term culture may reduce the number of donor Antigen presenting cells (APCs) (Barker et al 2004).
Classification of Stem cells:
The human body has an endogenous system of regeneration and repair through stem cells, where stem cells can be found almost in every type of tissue. This process is highly evolved through evolution, and so it is logical that restoration of function is best accomplished by these cells. Therefore, stem cells hold great promise for the future of translational medicine.
Stem cells can be classified into four broad types based on their origin, viz. stem cells from embryos; stem cells from the fetus; stem cells from the umbilical cord; and stem cells from the adult. Each of these can be grouped into subtypes. Some believe that adult and fetal stem cells evolved from embryonic stem cells and the few stem cells observed in adult organs are the remnants of original embryonic stem cells that gave up in the race to differentiate into developing organs or remained in cell niches in the organs which are called upon for repair during tissue injury (Anderson et al. 2001).
Stem cells applications:
Stem cells can be used to study development
Stem cells may help us understand how a complex organism evelops from a fertilised egg. In the laboratory, scientists can follow stem cells as they divide and become increasingly specialized, making skin, bone, brain, and other cell types. Identifying the signals and mechanisms that determine whether a stem cell chooses to carry on replicating itself or differentiate into a specialized cell type, and into which cell type, will help us understand what controls normal development.
Some of the most serious medical conditions, such as cancer and birth defects, are due to abnormal cell division and differentiation. A better understanding of the genetic and molecular controls of these processes may yield information about how such diseases arise and suggest new strategies for therapy.
Stem cells have the ability to replace damaged cells and treat disease
This property is already used in the treatment of extensive burns, and to restore the blood system in patients with leukaemia and other blood disorders.
Stem cells may also hold the key to replacing cells lost in many other devastating diseases for which there are currently no sustainable cures. Today, donated tissues and organs are often used to replace damaged tissue, but the need for transplantable tissues and organs far outweighs the available supply. Stem cells, if they can be directed to differentiate into specific cell types, offer the possibility of a renewable source of replacement cells and tissues to treat diseases including Parkinson's, stroke, heart disease and diabetes. This prospect is an exciting one, but significant technical hurdles remain that will only be overcome through years of intensive research.
Stem cells could be used to study disease
In many cases it is difficult to obtain the cells that are damaged in a disease, and to study them in detail. Stem cells, either carrying the disease gene or engineered to contain disease genes, offer a viable alternative. Scientists could use stem cells to model disease processes in the laboratory, and better understand what goes wrong.
Stem cells could provide a resource for testing new medical treatments
New medications could be tested for safety on specialized cells generated in large numbers from stem cell lines - reducing the need for animal testing. Other kinds of cell lines are already used in this way. Cancer cell lines, for example, are used to screen potential anti-tumour drugs.
Scope of the investigation:
Various neurodegenerative disorders were being managed by conventional medication therapy (i.e. Parkinson's disease, Alzheimer's disease, Huntington's disease, etc), but all these strategies are not efficient in preventing or reverting these progressive neurodegenerative processes. Recently, a new approach cell therapy has been introduced. This approach is based on the transplantation of appropriate cells, which must not only be well characterized and biologically and immunologically safe, but also sufficiently numerous to ensure adequate post-transplantation survival, tissue regeneration, and an acceptable degree of functional recovery and/or symptomatic improvement. For the first time in India, we have successfully isolated neural stem cells from the human fetuses of different gestations. The isolation and characterization of neural stem cells from the human fetuses open up a further interesting therapeutic perspective. The high regenerative potential of this area suggests that human fetuses are an ideal source of neural stem cells for neurodegenerative disease. Under our investigated conditions, the stem cells obtained from the human fetal brain, could be like embryonic stem cells or pluripotent cells proliferated in in vitro. Neural stem and progenitor cells have great potential for the treatment of neurological disorders. However, many obstacles remain to translate this field to the patient's bedside, including rationales for using neural stem cells in individual neurological disorders; the challenges of neural stem cell biology; and the caveats of current strategies of isolation and culturing neural precursors. Addressing these challenges is critical for the translation of neural stem cell biology to the clinic. Using neural stem cells would be yielded novel biologic concepts such as the importance of the reciprocal interaction between neural stem cells and the neurodegenerative environment. The prospect of using transplants of neural stem cells and progenitors to treat neurological diseases requires a better understanding of the molecular mechanisms of both neural stem cell behavior in experimental models and the intrinsic repair capacity of the injured brain.
Lacuna at present stem cells:
Much is left to be discovered and understood in all aspects of human biology. What have been frequently lacking are the tools necessary to make the initial discoveries, or to apply the knowledge of discoveries to the understanding of complex systems. These are some of the larger problems in basic and clinical biology where the use of stem cells might be the key to understanding, a new window on human developmental biology. The study of human developmental biology is particularly constrained by practical and ethical limitations. Human ES cells may allow scientists to investigate how early human cells become committed to the major lineages of the body; how these lineages lay down the rudiments of the body's tissues and organs; and how cells within these rudiments differentiate to form the myriad functional cell types which underlie normal function in the adult. The knowledge gained will impact many fields. For example, cancer biology will reap an especially large reward because it is now understood that many cancers arise by perturbations of normal developmental processes. The availability of human ES cells will also greatly accelerate the understanding of the causes of birth defects and thus lead directly to their possible prevention. Models of human disease that are constrained by current animal and cell culture models. Investigation of a number of human diseases is severely constrained by a lack of in vitro models. A number of pathogenic viruses including human immunodeficiency virus and hepatitis C virus grow only in human or chimpanzee cells. ES cells might provide cell and tissue types that will greatly accelerate investigation into these and other viral diseases. Current animal models of neurodegenerative diseases such as Alzheimer's disease give only a very partial representation of the disease's process
In Transplantation, Pluripotent stem cells could be used to create an unlimited supply of cells, tissues, or even organs that could be used to restore function without the requirement for toxic immunosuppression and without regard to tissue matching compatibility. Such cells, when used in transplantation therapies, would in effect be suitable for "universal" donation. Bone marrow transplantation, a difficult and expensive procedure associated with significant hazards, could become safe, cost effective, and be available for treating a wide range of clinical disorders, including aplastic anemia and certain inherited blood disorders. This would be especially important in persons who lost marrow function from toxic exposure, for example to radiation or toxic agents. Growth and transplant of other tissues lost to disease or accident, for example, skin, heart, nervous system components, and other major organs, are foreseeable.
In gene therapy, genetic material that provides a missing or necessary protein, or causes a clinically-relevant biochemical process, is introduced into an organ for a therapeutic effect. For gene-based therapies (specifically, those using DNA sequences), it is critical that the desired gene be introduced into organ stem cells in order to achieve long-term expression and therapeutic effect. Although techniques for delivering the therapeutic DNA have been greatly improved since the first gene therapy protocol almost 10 years ago, there are as yet no bona fide successes. Besides delivery problems, loss of expression or insufficient expression is an important limiting factor in successful application of gene therapy and could be overcome by transferring genes into stem cells (which presumably will then differentiate and target correctly).
Table-2: First successful Organ transplantations in Humans:
- 1905: First successful cornea transplant by Eduard Zirm
- 1954: First successful kidney transplant by Joseph Murray (Boston, U.S.A.).
- 1966: First successful pancreas transplant by Richard Lillehei and William Kelly (Minnesota, U.S.A.).
- 1967: First successful liver transplant by Thomas Starzl (Denver, U.S.A.).
- 1967: First successful heart transplant by Christiaan Barnard (Cape Town, South Africa).
- 1981: First successful heart/lung transplant by Bruce Reitz (Stanford, U.S.A.).
- 1983: First successful lung lobe transplant by Joel Cooper (Toronto, Canada).
- 1986: First successful double-lung transplant (Ann Harrison) by Joel Cooper (Toronto, Canada).
- 1987: First successful whole lung transplant by Joel Cooper (St. Louis, U.S.A.).
- 1995: First successful laparoscopic live-donor nephrectomy by Lloyd Ratner and Louis Kavoussi (Baltimore, U.S.A.).
- 1998: First successful live-donor partial pancreas transplant by David Sutherland (Minnesota, U.S.A.).
- 1998: First successful hand transplant (France).
- 2005: First successful partial facetransplant (France).
- 2005: First successful penis transplant (China).
- 2006: First jaw transplant to combine donor jaw with bone marrow from the patient, by Eric M. Genden (Mount Sinai Hospital, New York).
- 2008: First successful complete full double arm transplant (at the hospital Klinikum Rechts der Isar of the Technical University of Munich, Munich, Germany).
- 2008: First baby born from transplanted ovary.
- 2008: First transplant of a human windpipe using a patient's own stem cells.
The discovery of the stem cells in the central and Peripheral nervous system (CNS and PNS) is a relatively recent event. First, continued Neurogenesis (neuron generation) in the adult pointed to a long lived progenitor cell. Isolation of stem cells from the embryonic CNS, including basal forebrain, cerebral cortex, hippocampus, spinal cord and PNS as well as evidence for multipotent, stem like progenitors in vivo indicated that they are important components of developing nervous system (Rao 2006).
Continuous neurogenetic process is sustained by the life-long persistence of neural stem cells (NSCs) within restricted CNS areas. In the adult mammalian brain, the genesis of new neurons has been consistently documented in the sub granular layer of the dentate gyrus of the hippocampus and the sub ventricular zone (SVZ) of the lateral ventricles. The SVZ is the adult brain region with the highest neurogenetic rate, from which NSCs have been firstly isolated and characterized for their ability to give rise to non-neural cells. These cells, cell therapy are hope to one of the neurological disorder. Spinal cord injury (SCI) usually leads to devastating neurological deficits and disabilities (the annual incidence of SCI in the United States is estimated to be 40/million (Ali Samadikuchaksaraei 2007). Every year, India gets over 20,000 cases of spinal cord injury patients (Sachdeva SD 2008).
Recently Eftekhar et al explained cell replacement approaches in the recovery of SCI can be used to achieve two broad goals: 1) regeneration, which seeks to replace lost or damaged neurons and induce axonal regeneration or plasticity; and 2) repair, which seeks to replace supportive cells such as oligodendrocytes in order to induce remyelination and prevent progressive myelin loss. (Eftakarpour et al. 2008) Although Wrathall et al has indicated that in traumatic injured adult spinal cord induces the proliferative response of endogeneous glial precursors and progenitors and perhaps also pluripotent neural stem cells. Theses cells may prove to be an important new therapeutic target to improve recovery after injury to the spinal cord and brain (Wrathall et al. 2008). These approaches indicating that the need of neural stem cells and also supportive cells in cell based therapy of SCI.
Many sources of precursor's cells have been applied in the recovery of spinal cord but the most convincing preclinical results have been obtained with NPCs. But the use of cell based transplantation strategies for repair of chronic SCI remains unsolved. However these approaches have been to date most successful when applied in the sub acute phase of injury. However few drugs are able to influence functional outcome without having any improvement on cord pathology. Some drugs, however, can lessen cord pathology but fail to influence the functional outcome. The goal of future treatment options for SCI is therefore to find suitable new drugs or a combination of existing drugs and to use various cellular transplants, neurotrophic factors, myelin-inhibiting factors, tissue engineering and nano-drug delivery to improve both the functional and the pathological outcome in the injured patient. The application of cell based strategies for repair and regeneration of the chronically injured spinal cord will require a combinatorial strategy that will probably need to include approaches to overcome the effects of the glial scar, inhibitory molecule such as Rho and Nogo, and the use of tissue engineering strategies to bridge the lesion. Eftekhar et al reviewed that recent cell therapeutic strategies and his findings, on the uses of adult neural stem cell and progenitors cells for the repair of traumatic SCI and dysmyelinating disorders (Eftakarpour et al. 2008, Sharma 2008), Stephanie et al reported on cell therapy for spinal cord regeneration, methods of delivering cells to the injury site have evaluated, the advantages and disadvantages of each cell type are discussed along with the research studying each cell type. And suggestions have given for future investigation of Spinal cord regeneration(Stephanie et al. 2008). Further research is needed to improve and justify the clinical application of stem cell therapy. A thoughtful combination of stem cell therapy and CDT may have a chance of structural repair even in complete SCI. However, objective measures are needed to quantify improvement in MRI (anatomic measure), EMG (measuring of motor programs by sEMG, electrophysiologic measure), and measurements of coordination dynamics (kinesiologic measure) (Schalow et al. 2008).
Stem cells have also found use in Patients with Muscular or Bladder paralysis after Spinal Cord Injury. In patients with paraplegia, this therapy is of maximum use in patients 1-2 years after Spinal cord injury. It could also be potentially of use for patients with other neurological diseases of the spinal cord. In the future the therapy may be useful for patients with Brain damage also. Stem cells Injected directly into the Spinal fluid or around the spinal cord, at the site of injury has been found to improve nerve function. The Injection procedure was done under local anesthesia and is painless (Pandya 2008). Here, we reviewed different important opportunity sources of neural stem cells / progenitor cells for spinal cord injuries.
Classification of Stem cells
Stem cells can be classified into two major categories, according to their developmental status:
- Embryonic stem cells (ES): Embryonic stem cells are pluripotent cells and capable of giving rise to most tissues of the organism, including the germ line during development.
- Adult stem cells: Adult stem cells are specialized cells found with in many tissues of the body where they function in tissue homeostasis and repair.
Progenitor cells: These can include both stem cell and transient amplifying cells, or even cells that are well on the way to becoming differentiated.
Transient amplifying cells: Progeny of stem cells that undergo replication, but are not able to self renew and eventually give only one or more differentiated cell types.
Stem cell: Generally used to describe a cell that is capable both self renewal and differentiation.
Lineage: The natural progression from an immature cell type to one or differentiated cell type.
Lineage restriction: The inability of one lineage to give cell types of another, that is to cross lineage boundaries.
Cell fate: What a cell can do in either its natural location in the embryo or in an ectopic site. This is usually determined by making the cell in as neutral way as possible.
Totipotent: Able to give rise to all cell types .In mammals, only the fertilized egg and early cleavage stage blastomeres are truly totipotent. Cells of the inner cell mass and ES cells are unable to differentiate into cells of the trophectoderm lineage.
Pluripotent: Stem cells that can develop into any body cell type but can't become an entire human being. Stem cells from a seven-day-old embryo, or blastocyst.
Multipotent: Able to give rise to more than one differentiated cell type.
Unipotent: Cells can produce only one cell type, but have the property of self-renewal which distinguishes them from non-stem cells. eg: Hematopoetic Stem Cells
Induced pluripotent stem cells (iPS): Normal tissue cells induced to undifferentiated, pluripotent stem cells by transcriptional factors (OCT4, SOX2, NANOG, and LIN28) are defined as induced pluripotent stem cells (iPS).(eg fibroblasts cells.)
Somatic cell nuclear transfer (SCNT): Reprogramming the nucleus of an adult cell through transfer into the cytoplasm of an enucleated oocyte. This is referred to as cell nuclear replacement or somatic cell nuclear transfer. (eg: Dolly sheep).
Plasticity: The ability to cross lineage boundaries.
Embryonic stem cells:
Embryonic stem cells (ES cells [stage specific embryonic antigen marker SSEA]-3, -4) are pluripotent. They are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm (Fig-1). Human ESCs are derived from discarded, non-transferred human embryos, (Thomson et al. 1998) from the inner cell mass of a blastocyst using an immunosurgical technique. (Solter et al. 1975) Human neural stem cells / progenitor cells (derived from embryonic stem cells) differentiate into three neural lineages (neurons, astrocytes and oligodendrocytes) and are capable of forming mature progeny (Reubinoff et al. 2001) and also Dopamine neurons (Geraerts et al. 2007) in in vitro or in vivo. The clinical application of such embryonic neural stem cells would be limited by the potential rejection from another individual's immune system. To minimize this problem alternatively scientists developed individual's somatic nucleus transfer technique (SCNT). Recently ESC derived neural stem cells identified by CD133 biomarkers (Pruszak et al. 2007) were isolated by FACS. Compared to adult stem cells ES cells are clinically very effective for neurological disorders.
However the ES cells have some demerits such as in SCNT, not all of the donor cell's genetic information is transferred, the resulting hybrid cells retain those mitochondrial structures which originally belonged to the egg (eg: Dolly sheep had Hybrid DNA). Previously more than 120 ES cell lines have been reported world wide. ES cells lines are gradually degraded and will soon be useless for research. (ISSCF procs. Mumbai, 2005)
Some of the lines are genetically identical to others hence it has ethical issue; now only 11 cell lines remain available for research. Moreover, these cell lines have been grown on mouse feeder layers and are not suitable for clinical applications as there is an associated risk of virus transformation at the time of stem cell transplantation to cure various diseases. In clinical therapy large numbers of eggs for somatic cell nuclear transfer and the human embryos as a source of embryonic stem cells are extremely sensitive ethical issues. Currently, in India the use of spare human embryos from IVF programmers are permitted to be used for research only (ISSCF procs. Mumbai, 2005).
Adult stem cells:
Adult stem cells are precursor cells capable of differentiation into several different cells. They have been propagated from bone marrow, liver, brain, dental pulp, hair follicles, skin, skeletal muscle, adipose tissue, and blood (Cotsarelis et al. 1989, Cotsarelis et al. 1990, Dennis et al. 2002, Dobkin et al. 2006, Eglitis 1997, Graziadei et al. 1980) (Figure 2). In vitro they have been shown to differentiate into a wide variety of cell types such as osteoblasts, chondrocytes, endothelial cells, skeletal myocytes, glia, neurons, and cardiac myocytes.
Adult neural stem cells are undifferentiated cells found throughout the body that divide to replenish dying cells and regenerate damaged tissues. They can be found in children, as well as adults. Adult stem cells have abilities to divide or self-renew indefinitely and generate all the cell types of the organ from which they originate potentially regenerating the entire organ. Unlike embryonic stem cells, the use of adult stem cells in research and therapy is not controversial because the production of adult stem cells does not require the destruction of an embryo. Adult stem cells can be isolated from a tissue sample obtained from an adult. They have mainly been studied in humans and model organisms such as mice and rats.
Neural stem cells:
Self-renewing multipotent Neural Stem Cells (NSCs) have been isolated and characterized from various areas such as the adult Central Nervous System (CNS) including the spinal cord, and from various species, including human (biopsies and post-mortem tissues). Adult-derived neural progenitor and stem cells have been transplanted in animal models, and shown functional engraftment, supporting their potential use for therapy. (Graziadei et al. 1980)
The immunology of grafted stem cells has not been extensively studied in depth, when grafting tissue of different immunological disparity, there is local cytokine production that may affect the stability and development of stem cells. The effects of hibernation on the antigenicity of the tissue are not known, although short-term culture may reduce the number of donor Antigen presenting cells (APCs). It is predicted that rejection will occur with many different types of stem cells, especially ES and non-neural stem cells. It has been suggested that the brain and related tissue, such as the eye, contain locally immunosuppressive factors and this includes TGF-β and related cytokines which as a family act locally as anti-inflammatory, antimitotic, down regulatory cytokines, with TGF-β itself being the endogenous ligand for the immunophilins. In addition, the internal milieu of the brain has been suggested to favor tolerance development or anergia, although the conditions may change after local trauma and inflammation. Factors that have been implicated in this latter process are inducible FAS/FAS-L expression in the brain after trauma, leading to the induction of cell death of invading lymphocytes. (Barker et al. 1997, Streilein 1993, Wang et al. 1994, Brabb et al. 2000 Bechmann et al. 1999). However, the technique is far from being standardized and several studies have failed to reach the same results. The privileged status of the brain is now regarded as the result of a balance of regulated events that produces either immune privilege or effective responses (Widner et al 1998, Hickey et al 2001). In terms of neural grafting, there are several factors that contribute to the timing and intensity of the rejection response and this includes the type of graft transplanted, the degree of immunological disparity between donor and recipient, and how and where the tissue is implanted (Roger et al 2004). Although the question is whether neurons or nervous system cells derived from ES cells behave similar or differently from embryonic, fetal and adult stem cells, although this question remains largely unanswered, a growing body of work is beginning to suggest functional difference .However the ES cell transplantation can directly modulate the immune response. Wesselschmidt and McDonald were observed that a 50% reduction in the number of macrophages responding to ES cell transplantation compared with Sham-transplanted animals (Rao 2006).
Site/origin of neural stem cells:
In the mammalian adult brain, the genesis of new neurons continues throughout life within two 3-layered cortical regions, the hippocampus and olfactory bulb (OB), where it is sustained by endogenous stem cells. The most active Neural Stem Cells (NSC) compartment is found in Sub ventricular zone (SVZ) (Fig-3). This area represents a remnant of the embryonic germinal neuroepithelium, which persists throughout life as an actively mitotic layer in the wall of the telencephalic lateral ventricles and along its rostral extension toward the olfactory bulb. A complete turnover of the resident proliferating cell population occurs every 12 to 28 days in the SVZ about 30,000 new neuronal precursors (neuroblasts) being produced every day and migrating to the OB (Galli et al. 2003). Two main cell types are found in the SVZ: migratory, proliferating neuroblasts and astrocytes. They reach the more superficial OB layers and terminally differentiate into granule and periglomerular neurons. Glial tubes are composed of a special type of astroglia that expresses the marker of mature Central Nervous System (CNS) astrocytes (glial fibrillary acidic protein (GFAP)) but also contain the cytoskeletal proteins vimentin and nestin. Astroglial tubes and NSCs do not coexist solely within the periventricular aspect of the SVZ but also within the rostral migratory stream that extends into the OB, with the former perhaps contributing to create an appropriate stem cell "niche" for the maintenance of NSCs all along the pathway. Adult neurogenesis is a spatially confined process, constrained within the boundaries of the brain-deep SVZ (inner side of the sub Ventricular zone layer). Astrocytes and ependymal cells of the SVZ may act as "stromal" elements of the CNS by producing molecules as bone morphogenetic proteins that affect the neuronal versus glial fate of the stem/progenitor cells. Furthermore, the extra cellular matrix of the SVZ contains tenascin and proteoglycans, molecules that are important in the formation of developmental compartments and in the control of cell adhesion, migration and differentiation. The proximity of the SVZ with the cerebrospinal fluid, the enlarged intercellular spaces, the reduced cell-cell contacts, and the presence of molecules linked to water co-transport contribute to create in the SVZ a cytoarchitectural / biochemical niche, which is very different from the environment of the mature CNS parenchyma (Galli et al 2003). In recent years, neurogenesis was reported to occur in other regions of the adult brain under normal conditions, such as neocortex, amygdala, and substantia nigra. However, other research groups were not able to replicate some of these reports (Hermann et al 2006).
However, the organization of the adult SVZ in humans is different from that in other mammalian species. The lateral ventricular wall consists of four layers with various thickness and cell densities: a monolayer of ependymal cells (layer I), a hypocellular gap containing astrocytic processes (layer II), a ribbon of cells composed of astrocytes (layer III), and a transitional zone into the brain parenchyma (layer IV). Astrocytes proliferate in vivo and behave as multipotent progenitors in vitro, but no chain migration was observed in the human SVZ. However, newborn cells that express cell cycle proteins (Ki-67 and proliferating cell nuclear antigen [PCNA]) were detected in the granular and glomerular layers of the human OB, but no clear evidence of the presence of a migratory pathway from the SVZ has been demonstrated. Therefore, it was suggested that individual cells might migrate separately to the OB. These results indicate that in comparison with rodents, precursor cells in the human OB are rare but not completely absent (Geraerts et al 2007). However, these endogenous neural stem cells are very difficult to isolate sufficient total number of cells from an individual patient's brain tissue for immediate cell therapy.
Isolation and culturing of neural stem cells:
The neural stem cells isolated and expanded from the embryonic and adult mouse striatum in the early 1990's in a culture system referred to as the Neurosphere Assay (Reynolds et al 1992).
Later found that not only embryonic CNS but also adult CNS in vitro possesses the ability to generate neurospheres forming cells in vitro, including Neural Epithelial progenitor Cells (NEP) cells, radial glial cells, SVZ cells, and ependymal cells, to date, the existence of cells that clonigenically generate neurons, astrocytes and oligodendrocytes in vivo (Mahender 2006). Mahender provided compelling evidence that after exposure to high concentrations of Epidermal growth factor (EGF) mitogen, type C amplifying progenitors of the adult SVZ function as stem cells in vitro (Rao 2006). Here clearly indicated that transformed cells do not possess stem cell characteristic in vivo. Ependymal cells, astrocytes, oligodendrocyte precursors and neural progenitor cells can form neurospheres like aggregates that can be passeged for a limited time period. Most studies have shown the neural stem cells derived from the brain respond to either basic fibroblast growth factor (bFGF) or EGF (Fig-4) and Neural stem cells cultured as neurospheres from the early embryonic forebrain do not respond to EGF until they acquire EGF receptors at later stages of development in vitro or in vivo. However, neural stem cells cultures from the adult murine hippocampus forms as monolayer in the presence of bFGF (Kornblum et al. 1998).
These neurospheres produce repeated passages containing self renewing, proliferating and differentiating cells, typically presenting prominin -1 cell surface antigen which is also know as Cluster of differentiation CD 133 and these cells are uniquely separated directly by magnetic beads conjugated with antibodies (MACS) or fluorescence assay cell sorting (FACS) by negative selection of CD 34 - and CD 45 - antigen markers cells (CD133+CD34-CD45-). These cells upon transplantation into brains of immunodeficient neonatal mice, the sorted /expanded CD133+ cells showed potent engraftment, proliferation, migration, and neural differentiation (Uchida et al. 2000). However previously, stem like cells have purified from various organs as side population (SP) cells, based on their property to exclude Hoechst 33342 (Goodell et al. 1997).
Characteristic of neural stem cells:
Proliferating cell population in the adult CNS share the expression of a number of universal markers, such as Nestin, Notch1, SoX2, Musashi, and so forth, with embryonic ventricular zone stem cells, were raising the possibility that these molecules involve in the consolidation of neural fate during primary neural induction, and also play a role in adult neurogenesis. Notch pathway appears to play an essential role in the maintenance of a stem /progenitor cell pool a well as play an role in regulating asymmetric vs symmetric division, both during embryogenesis and in adult hood, expression of Notch 1 or one of its down stream regulators such as HES-1 inhibits neural differentiation and results in the maintenance of a progenitor state (Rao 2006). Kornblum et al were reviewed that numerous specific genes/pathways have been identified as important regulators of neural stem cell proliferation, many of which are important for several other cell types, including other stem cells. Some of these are: Bmi-I, P21, nucleostemin, maternal embryonic leucine zipper kinase, P53, Rb, and Akt among others (Kornblum et al.1998). Several reports demonstrated that plasticity of neural stem cells outside of the CNS. Hence the alternative sources for neural stem cells could be other than the Patients CNS like Autologous ESC, Olfactory epithelial sheath cells (OECS), Bone marrow derived stem cells ,Cord blood, Adipose tissue, Skin dermis, Hair follicles and Wharton jelly cells, and heterologus tissue stem cells like aborted Fetal -brain, neural crest derived cells. Among these embryonic derived neural stem cells have very good characteristic features present for applications but the social awareness and political issues may be slowing down the human clinical applications. Hence, the alternative sources for embryonic stem cells have been exploited for the neural stem cells isolation and some of them are in Phase I and Phase II clinical trails (example bone marrow derived cells).
- Regeneration, which seeks to replace lost or damaged neurons and induce axonal regeneration or plasticity.
- Repair which seeks to replace supportive cells such as oligodendrocytes in order to induce remyelination and prevent progressive myelin loss. Alternatively, cell transplantation may promote protection of endogenous cells from further secondary injury. Although the presence of developmental inhibitory or repulsive cues such as Netrin1, semaphorin 4D, and ephrin B3 in the adult CNS may complicate the successful restoration of various neuronal components of the spinal cord at the injury site, the specificity of oligodendrocytic cell death in white matter pathologies has attracted attention as a translationally relevant target for experimental SCI treatments (Eftakarpour et al.2008).
Alternative sources of Neural stem cells/progenitor cells for cell therapy:
Olfactory ensheathed cells (OECs) / Olfactory mucosa cells:
The nose contains neurons that send signals to the brain when triggered by odor molecules. The axons of these neurons are enveloped by Olfactory ensheathed cells (OECs), a special type of neuronal support cells (Glial cells) (Doucette et al. 1995) that guides the axons and supports their elongation. The bundles travel from the nose to the brain's olfactory bulb, where they make connections with other neurons. Because olfactory tissue is exposed to the external environment (i.e., the air we breathe), it contains cells with considerable regeneration potential, including renewable neurons, progenitor/ stem cells, and OECs. Through a relatively innocuous biopsy procedure, olfactory tissue can be obtained from the nasal cavity. It can also be retrieved from the olfactory bulb, but this requires an invasive penetration of the cranial cavity that although unsuitable for human patients has been the procedure for most of the supporting animal research.
Problems of rejection, overgrowth, disease transmission and ethical issues can be avoided because a person's own olfactory mucosa can be used. OECs theoretically promote axonal regeneration by producing insulating myelin sheaths around growing and damaged axons, secreting growth factors, and generating structural and matrix macromolecules that lay the tracks for axonal elongation.
These properties have led to an increasing use of olfactory ensheathing cells in preclinical models of transplantation for spinal cord repair including complete transection, hemisection, tract lesion, and contusion with over 50 published studies in the last 10 years. (Barnett et al 2004).
Nasal olfactory ensheathing cells transplants assist recovery after spinal cord injury, including complete transaction ( Lu et al. 2001, Ramer et al. 2004) and there is evidence that adult olfactory tissue is effective when transplanted 1 month after spinal cord transection in the rat. (Lu et al. 2002) According to the promising results obtained from animal experiments, several clinical trials started. In a large series more than 400 patients underwent transplantation of fetal olfactory bulb-derived cells, of which the results of 171 operations were published. (Huang et al 2006) A single-blinded, controlled trial has established the safety and feasibility of intraspinal transplantation of autologous olfactory ensheathing cells in human spinal cord injury. This is a report of the outcome of the trial 1 year after transplantation. (Féron et al 2005). The safety and efficacy shown by researchers in implantation procedure are unclear. Patients have encountered serious medical complications and no lasting increase in sensory, motor function or functional ability (Dobkin et al 2006). Controversial medical risks of people living with serious disability from SCI and a way to overcome the limited expectations they perceive within their medical systems. However, recently that Electrophysiological evidence of olfactory cell transplants, improving the function of spinal cord injury is published.) (Toft et al 2007).
However when sampling of the transplanted OECs in to the spinal cord needs to be removed for transplantation studies from olfactory mucosa, resulted permanent damage to olfaction (smelling). Portugal's Dr. Carlos Lima implants whole olfactory tissue obtained from the patient at the injury site. Lima believes that more than one cell type is needed to maximize regeneration, including not only OECs but also olfactory neurons and stem cells play a role. In another study, an Australian team implants OECs, isolated and cultured from the patient's nasal tissue. Dr.Huang (China) transplants OECs isolated from fetal olfactory bulbs. In Portuguese and Australian procedures, no immunological rejection of the transplanted tissue occurred as it was analogous tissues used for transplantation (http://www.healingtherapies.info).
Whereas Huang's procedure fetal-tissue's undifferentiated nature minimizes immunological rejection (Huang et al 2006). Feron et al tested the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. Olfactory ensheathing cells were grown and purified in vitro from nasal biopsies and injected by microinjection. 12 to 28 million cells were injected into the region of damaged spinal cord. One year after cell implantation, there were no medical, surgical or other complications were developed to indicate that the procedure is unsafe. There was no evidence of spinal cord damage nor of cyst, syrinx or tumor formation. In this clinical examination, there was no naturopathic pain reported by the participants, no change in psychosocial status and no evidence of deterioration in neurological status. This indicates that the olfactory ensheathing cells transplantation may be a safe method by invitro propagation before transplantation. (Féron et al 2005). However in recent reports others OECs cell transplantations clinicals have showed some adverse effects. Chen L et al, reported that his Sixteen patients out of 327 (4.9%) experienced the various complications including headache, short-term fever, seizure attack, central nerve system infection, pneumonia, respiratory failure, urinary tract infection, heart failure, and possible pulmonary embolism; of them, there were 4 deaths (1.2%) (Chen et al. 2007). Chew et al. reported that a woman who received an injection into each frontal lobe in Beijing, China. Her ALS progressed at a more rapid rate after the procedure and she suffered disabling side-effects (Chew et al. 2007). In Mackay-Sim trial Phase I/IIa was designed to test the feasibility and safety of transplantation of autologous olfactory ensheathing cells into the injured spinal cord in human paraplegia. There were no adverse findings 3 years after autologous transplantation of olfactory ensheathing cells into spinal cords injured at least 2 years prior to transplantation. The magnetic resonance images (MRIs) at 3 years showed no change from preoperative MRIs or intervening MRIs at 1 and 2 years, with no evidence of any tumor of introduced cells and no development of post-traumatic syringomyelia or other adverse radiological findings. There were no significant functional changes in any patients and no neuropathic pain. In one transplant recipient, there was an improvement over 3 segments in light touch and pin prick sensitivity bilaterally, anteriorly and posteriorly. They concluded that transplantation of autologous olfactory ensheathing cells into the injured spinal cord is feasible and is safe up to 3 years of post-implantation; however, this conclusion should be considered preliminary because of the small number of trial patients (Mackay-Sim et al. 2008).
Bone marrow (BM):
The bone marrow stroma contains mesenchymal stem cells (also called marrow stromal cells). These cells are multip