Stem Cells: History, Properties and Research

History

Stem cells are cells found in all multi cellular organisms. They are characterized by the ability to renew themselves through mitotic cell division and differentiate into a diverse range of specialized cell types. Research in the stem cell field grew out of findings by Ernest A. McCulloch and James E. Till at the University of Toronto in the 1960s

The two broad types of mammalian stem cells are: embryonic stem cells that are isolated from the inner cell mass of blastocysts, and adult stem cells that are found in adult tissues. In a developing embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialized cells, but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

Stem cells can now be grown and transformed into specialized cells with characteristics consistent with cells of various tissues such as muscles or nerves through cell culture. Highly plastic adult stem cells from a variety of sources, including umbilical cord blood and bone marrow, are routinely used in medical therapies. Embryonic cell lines and autologous embryonic stem cells generated through therapeutic cloning have also been proposed as promising candidates for future therapies

Contents (Jump to)

1 Properties

1.1 Self-renewal

1.2 Potency definitions

1.3 Identification

2 Embryonic

3 Adult

4 Amniotic

5 Induced pluripotent

6 Lineage

7 Treatments

8 Research patents

9 Key research events

10 References

Properties

The classical definition of a stem cell requires that it possess two properties:

Self-renewal – the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.

Potency – the capacity to differentiate into specialized cell types. In the strictest sense, this requires stem cells to be either totipotent or pluripotent – to be able to give rise to any mature cell type, although multipotent or unipotent progenitor cells are sometimes referred to as stem cells.

Self-renewal

Two mechanisms exist to ensure that the stem cell population is maintained:

Obligatory asymmetric replication – a stem cell divides into one daughter cell that is identical to the original stem cell, and another daughter cell that is differentiated

Stochastic differentiation – when one stem cell develops into two differentiated daughter cells, another stem cell undergoes mitosis and produces two stem cells identical to the original.

Potency definitions

Pluripotent, embryonic stem cells originate as inner mass cells within a blastocyst. The stem cells can become any tissue in the body, excluding a placenta. Only the morula’s cells are totipotent, able to become all tissues and a placenta.

Human embryonic stem cells

A: Cell colonies that are not yet differentiated.

B: Nerve cell

Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.

Totipotent (a.k.a omnipotent) stem cells can differentiate into embryonic and extraembryonic cell types. Such cells can construct a complete, viable, organism. These cells are produced from the fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent.

Pluripotent stem cells are the descendants of totipotent cells and can differentiate into nearly all cells, i.e. cells derived from any of the three germ layers.

Multipotent stem cells can differentiate into a number of cells, but only those of a closely related family of cells.

Oligopotent stem cells can differentiate into only a few cells, such as lymphoid or myeloid stem cells.

Unipotent cells can produce only one cell type, their own, but have the property of self-renewal which distinguishes them from non-stem cells (e.g. muscle stem cells).

Identification

The practical definition of a stem cell is the functional definition – a cell that has the potential to regenerate tissue over a lifetime. For example, the gold standard test for a bone marrow or hematopoietic stem cell (HSC) is the ability to transplant one cell and save an individual without HSCs. In this case, a stem cell must be able to produce new blood cells and immune cells over a long term, demonstrating potency. It should also be possible to isolate stem cells from the transplanted individual, which can themselves be transplanted into another individual without HSCs, demonstrating that the stem cell was able to self-renew.

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Properties of stem cells can be illustrated in vitro, using methods such as clonogenic assays, where single cells are characterized by their ability to differentiate and self-renew. As well, stem cells can be isolated based on a distinctive set of cell surface markers. However, in vitro culture conditions can alter the behavior of cells, making it unclear whether the cells will behave in a similar manner in vivo. Considerable debate exists whether some proposed adult cell populations are truly stem cells.

Embryonic

Embryonic stem cell lines (ES cell lines) are cultures of cells derived from the epiblast tissue of the inner cell mass (ICM) of a blastocyst or earliermorula stage embryos. A blastocyst is an early stage embryo-approximately four to five days old in humans and consisting of 50-150 cells. ES cells are pluripotent and give rise during development to all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or the placenta.

Nearly all research to date has taken place using mouse embryonic stem cells (mES) or human embryonic stem cells (hES). Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin and require the presence of Leukemia Inhibitory Factor (LIF). Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts(MEFs) and require the presence of basic Fibroblast Growth Factor (bFGF or FGF-2). Without optimal culture conditions or genetic manipulation, embryonic stem cells will rapidly differentiate.

A human embryonic stem cell is also defined by the presence of several transcription factors and cell surface proteins. The transcription factors Oct-4,Nanog, and Sox2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency. The cell surface antigens most commonly used to identify hES cells are the glycolipids SSEA3 and SSEA4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.

After nearly ten years of research, there are no approved treatments using embryonic stem cells. The first human trial was approved by the US Food & Drug Administration in January 2009. However, as of August 2010, the first human trial had not yet been initiated. Although, The first human medical trial for embryonic stem cells started in Atlanta on October 13, 2010 for spinal injury victims. ES cells, being pluripotent cells, require specific signals for correct differentiation – if injected directly into another body, ES cells will differentiate into many different types of cells, causing a teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face. Many nations currently have moratoria on either ES cell research or the production of new ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for regenerative medicine and tissue replacement after injury or disease.

Adult

Also known as somatic stem cells and germline (giving rise to gametes) stem cells, they can be found in children, as well as adults.

Stem cell division and differentiation. A – stem cell; B – progenitor cell; C – differentiated cell; 1 – symmetric stem cell division; 2 – asymmetric stem cell division; 3 – progenitor division; 4 – terminal differentiation

Pluripotent adult stem cells are rare and generally small in number but can be found in a number of tissues including umbilical cord blood. A great deal of adult stem cell research has focused on clarifying their capacity to divide or self-renew indefinitely and their differentiation potential. In mice, pluripotent stem cells are directly generated from adult fibroblast cultures. Unfortunately, many mice don’t live long with stem cell organs.

Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell,endothelial stem cell, etc.).

Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants. Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.

The use of adult stem cells in research and therapy is not as controversial as embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Additionally, because in some instances adult stem cells can be obtained from the intended recipient, (an autograft) the risk of rejection is essentially non-existent in these situations. Consequently, more US government funding is being provided for adult stem cell research.

An extremely rich source for adult mesenchymal stem cells is the developing tooth bud of the mandibular third molar. While considered multipotent they may prove to be pluripotent. The stem cells eventually form enamel (ectodrm), dentin,periodontal ligament, blood vessels, dental pulp, nervous tissues, including a minimum of 29 different unique end organs. Because of extreme ease in collection at 8-10 years of age before calcification and minimal to no morbidity will probably constitute a major source for personal banking, research and multiple therapies. These stem cells have been shown capable of producing hepatocytes.

Amniotic

Multipotent stem cells are also found in amniotic fluid. These stem cells are very active, expand extensively without feeders and are not tumorigenic. Amniotic stem cells are multipotent and can differentiate in cells of adipogenic, osteogenic, myogenic, endothelial, hepatic and also neuronal lines. All over the world, universities and research institutes are studying amniotic fluid to discover all the qualities of amniotic stem cells, and scientists such as Anthony Atala and Giuseppe Simoni have discovered important results.

From an ethical point of view, stem cells from amniotic fluid can solve a lot of problems, because it’s possible to catch amniotic stem cells without destroying embryos. For example, the Vatican newspaper “Osservatore Romano” called amniotic stem cell “the future of medicine”.

It’s possible to collect amniotic stem cells for donors or for autologuous use: the first US amniotic stem cells bank  opened in Medford, MA, by Biocell Center Corporation  and collaborates with various hospitals and universities all over the world

Induced pluripotent

These are not adult stem cells, but rather reprogrammed cells (e.g. epithelial cells) given pluripotent capabilities. Using genetic reprogramming with protein transcription factors, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue. Shinya Yamanaka and his colleagues at Kyoto University used the transcription factors Oct3/4, Sox2, c-Myc, and Klf4 in their experiments on cells from human faces. Junying Yu, James Thomson, and their colleagues at the University of Wisconsin-Madison used a different set of factors, Oct4, Sox2, Nanog and Lin28, and carried out their experiments using cells from human foreskin.

As a result of the success of these experiments, Ian Wilmut, who helped create the first cloned animal Dolly the Sheep, has announced that he will abandon nuclear transfer as an avenue of research.

Frozen blood samples can be used as a source of induced pluripotent stem cells, opening a new avenue for obtaining the valued cells.

Lineage

They ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.

An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular niche. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies in Drosophila germarium have identified the signals dpp and adherens junctions that prevent germarium stem cells from differentiating.

Main article: Induced Pluripotent Stem Cell

The signals that lead to reprogramming of cells to an embryonic-like state are also being investigated. These signal pathways include several transcription factors including the oncogene c-Myc. Initial studies indicate that transformation of mice cells with a combination of these anti-differentiation signals can reverse differentiation and may allow adult cells to become pluripotent. However, the need to transform these cells with an oncogene may prevent the use of this approach in therapy.

Challenging the terminal nature of cellular differentiation and the integrity of lineage commitment, it was recently determined that the somatic expression of combined transcription factors can directly induce other defined somatic cell fates; researchers identified three neural-lineage-specific transcription factors that could directly convert mouse fibroblasts (skin cells) into fully-functional neurons. This “induced neurons” (iN) cell research inspires the researchers to induce other cell types implies that all cells are totipotent: with the proper tools, all cells may form all kinds of tissue.

Treatments

Medical researchers believe that stem cell therapy has the potential to dramatically change the treatment of human disease. A number of adult stem cell therapies already exist, particularly bone marrow transplants that are used to treat leukemia. In the future, medical researchers anticipate being able to use technologies derived from stem cell research to treat a wider variety of diseases including cancer, Parkinson’s disease, spinal cord injuries, Amyotrophic lateral sclerosis, multiple sclerosis, and muscle damage, amongst a number of other impairments and conditions. However, there still exists a great deal of social and scientific uncertainty surrounding stem cell research, which could possibly be overcome through public debate and future research, and further education of the public.

One concern of treatment is the possible risk that transplanted stem cells could form tumors and have the possibility of becoming cancerous if cell division continues uncontrollably.

Stem cells, however, are already studied extensively. While some scientists are hesitant to associate the therapeutic potential of stem cells as the first goal of the research, they find the investigation of stem cells as a goal worthy in itself.

Contrarily, supporters of embryonic stem cell research argue that such research should be pursued because the resultant treatments could have significant medical potential. It is also noted that excess embryos created for in vitro fertilization could be donated with consent and used for the research

Diseases and conditions where stem cell treatment is promising or emerging. Bone marrow transplantation is, as of 2009, the only established use of stem cells.

Research patents

The patents covering a lot of work on human embryonic stem cells are owned by the Wisconsin Alumni Research Foundation (WARF). WARF does not charge academics to study human stem cells but does charge commercial users. WARF sold Geron Corp. exclusive rights to work on human stem cells but later sued Geron Corp. to recover some of the previously sold rights. The two sides agreed that Geron Corp. would keep the rights to only three cell types. In 2001, WARF came under public pressure to widen access to human stem-cell technology.

These patents are now in doubt as a request for reviewing the US Patent and Trademark Office has been filed by non-profit patent-watchdogs The Foundation for Taxpayer Consumer Rights, and the Public Patent Foundation as well as molecular biologist Jeanne Loring of the Burnham Institute. According to them, two of the patents granted to WARF are invalid because they cover a technique published in 1993 for which a patent had already been granted to an Australian researcher. Another part of the challenge states that these techniques, developed by James A. Thomson, are rendered obvious by a 1990 paper and two textbooks.

The outcome of this legal challenge is particularly relevant to the Geron Corp. as it can only license patents that are upheld.

Key research events

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 previously developed iPS cells and not tumorigenic, moreover genes that are required for iPS cells do not need to be inserted into specific sites, which encourages 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.

1 March 2009 – Andras Nagy, Keisuke Kaji, et al. discover a way to produce embryonic-like stem cells from normal adult cells by using a novel “wrapping” procedure to deliver specific genes to adult cells to reprogram them into stem cells without the risks of using a virus to make the change. The use of electroporation is said to allow for the temporary insertion of genes into the cell.

28 May 2009 Kim et al. announced that they had devised a way to manipulate skin cells to create patient specific “induced pluripotent stem cells” (iPS), claiming it to be the ‘ultimate stem cell solution’.

11 October 2010 First trial of embryonic stem cells in humans

References

Becker AJ, McCulloch EA, Till JE (1963). “Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells”. 

Siminovitch L, McCulloch EA, Till JE (1963). “The distribution of colony-forming cells among spleen colonies”. Journal of Cellular and Comparative Physiology.

Tuch BE (2006). “Stem cells-a clinical update”. Australian Family Physician.

Hans R. Schöler (2007). “The Potential of Stem Cells: An Inventory”. In Nikolaus Knoepffler, Dagmar Schipanski, and Stefan Lorenz Sorgner. Humanbiotechnology as Social Challenge. Ashgate Publishing, Ltd.

Mitalipov S, Wolf D (2009). “HYPERLINK “http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2752493″Totipotency, pluripotency and nuclear reprogrammingHYPERLINK “http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2752493″”. Adv Biochem Eng Biotechnol 

Ulloa-Montoya F, Verfaillie CM, Hu WS (Jul 2005). “Culture systems for pluripotent stem cells”. J Biosci Bioeng. 

Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Ruadkow IA (1974). “Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method”.