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Is stem cell therapy a viable option for treatment of cardiac disease?
- Delivery methods developed
- Cell types used has changed
- First gen therapy
- Cell derived theory to cell mediated theory through paracrine effect
- Next gen trials – controversy
- Whats next?
Cardiac disease is the leading cause of death in both the UK and worldwide. The estimated cost is set to rise from $656bn to $1208bn in the next 15 years putting the global healthcare system under immense pressure (Go et al., 2014). Stem cells (SCs) emerged as a potential treatment method and have been in clinical use for over a decade within cardiac treatment. Many variations between cell type, delivery method, timing, number of cells, homing and grafting highlight stem cell therapy is plagued with unresolved issues (Shim et al., 2013). Whether the SC treatment is for acute myocardial infarction (AMI) or for coronary heart failure (CHF) its main therapeutic aim is to repopulate the loss of 1bn cardiomyocytes and supporting cells.
Cell Types Used
Adult SCs used can be categorised into; bone marrow (BM) derived, circulating and resident to the heart. BM include bone marrow mononuclear SCs (BMMNCs) and mesenchymal SC (MSCs). Circulating SCs are represented by endothelial progenitor cells (EPCs) which have been shown to restore blood flow to necrotic myocardium, whilst cardiac stem cells (CSCs) purified from myocardium are believed to hold cardiac regeneration abilities (Mirotsou et al., 2011).
3 distinct delivery methods have been established (fig 1). The non-invasive and straight forward route is intracoronary infusion but has issues including microvasculature occlusion. Direct or catheter based intramyocardial injection allows inserted cells to enter the infarcted region increasing grafting and homing of cells to myocardium. Administration via catheter is the most common delivery method amongst trails due to its cost effectiveness and repeatability. Moreover, direct intramyocardial injection during surgery has ethical issues relating to running a control group with sham surgery, but has been shown to result in greater engraftment especially for larger cells such as MSCs (Chong and Murry, 2014).
Figure 1 - Current cell delivery routes; 1) Intracoronary infusion using an over the-wire balloon catheter 2) Intramuscular injection via catheter or 3) direct injection into the myocardium during surgery (Dimmeler et al., 2005).
First Generation Trials
First generation BMMNC based trials for AMI with intracoronary had the common aim of establishing if BMMNCs were capable of improving cardiac function. Varying results highlight the difficulty in drawing conclusions from the data. A collection of trials (Strauer et al, TOPCARE AMI, BOOST & Fernandez et al ) reported practically identical results; 7–9% improvement in global LV ejection fraction, significantly reduced end-systolic LV volumes, and improved perfusion in the infarcted area 4–6 months after cell transplantation (Shim et al., 2013). Whilst similar trials (TIME, Late TIME, HEBE, ASTMAI & Leuven AMI) reported no significant change in cardiac function (Behfar et al., 2014). Proposed reasons for result variations include cell timing administration and preparation. Furthermore, meta-analysis has highlighted a correlation between number of discrepancies within a trial and the improvement in LV function ( P = 0.005), furthermore the group of studies with no discrepancies (none of the above) reported no improvement in LV function (Nowbar et al., 2014). This raises the question, do BMMNCs really improve LV function or is there another reason?
Physical replacement of damaged cells with transplanted ones was the initial target of SC therapy. Now, research focus has moved towards harnessing endogenous repair mechanisms of the transplanted cells through a paracrine effect (Menasché, 2014). This was believed to be the case as the number of SCs which regenerate in the myocardium following transplantation cannot account for the level of improvement (Mirotsou et al., 2011).
Rat models using MSCs have shown soluble factors improve cardiac function. In particular, Fidelis-de-Oliveira et al illustrated through isolating MSCs cultured medium (CM) following hypoxic conditions (hypoxia induces increased release of growth/angiogenic factors, cytokines and vascular endothelial growth factor) promoted significant reductions in LVEDP (35%), Cardiac contractility and relaxation improvements (15% and 12% respectively) compared to CM under normoxia conditions (Fidelis-de-Oliveira et al., 2012). The results show soluble factors released by MSCs are able to improve cardiac function following AMI.
Doyle et al showed that conditioned media from EPCs could improve cardiac function in a porcine model following AMI (fig 2). The exact mechanisms are unknown, but soluble factors such as VGEF, IGF 1 and TGFβ1 secreted by EPCs with cardiotrophic and neoangiogenic effects are believed to be responsible for the infract related remodelling following MI (Doyle et al., 2008).
Figure 2 - Changes in infarct related regions following AMI from baseline to 2 months post-therapy. Comparison across range of structure and functions known to be damaged following MI, and comparison of treatment with endothelial progenitor cells (EPC), conditioned media (CM) derived from EPCs and standard control. Grey bars are pre-treatment. Black bars indicate post-treatment. *p < 0.05 for comparison of baseline to 2 months post-therapy.
Next generation trials
A distinct change in the biologic agents used from non-cardiac (BMMNCs/MSCs/EPCs) to cardiac committed cells (CSCs e.g. cardiospheres) has occurred, beginning with the first in human trial of CSCs harvested and transplanted during coronary artery bypass surgery (CABG) – SCIPIO Trial. Interim results showed that LVEF and EF in the CSC infused region of infarct myocardium improved for CSC treated groups. Cardiac magnetic resonance (CMR) showed a significant increase in LVEF from 27.5±1.6% [P=0.004 n=8] at 4 months to 35.1±2.4% [P=0.013, n=5] at 12 months after CSCs infusion (figure 4). Though the patient numbers are low, these findings represent a significant breakthrough in the field and show a marked improvement in global and regional LV function especially over time, indicating cardiac regeneration is possible (Chugh et al., 2012).
Figure 4 – Data from SCIPIO Trial. Left Ventricular Ejection Fraction (LVEF) at baseline (27.5±1.6%), 4 months after cardiac stem cell (CSC) infusion (35.1±2.4%), and 12 months after CSC infusion (41.2±4.5%) (Chugh et al., 2012).
Controversy Around SCIPIO Trial
In April this year, the editors of the original paper (The Lancet) issued an expression of concern regarding the integrity of two supplementary figures published online which were carried out at a separate institution from the main trial. Although they do not impact the findings directly, the controversy around them has casted doubt over the entire trial. A large number of clinical trials have been designed based on the SCIPIO trials results (cited 270 times), with a similar trial (CADUCEUS) unable to reproduce their findings of improved LV function following CSC transplant, though they did find a reduction in scare tissue following MI (Makkar et al., 2012).
The inability to repeat results and recent expression of concern highlight the difficulties in the next generation cell therapy trials face. Further trials in different labs with higher patient numbers are required to determine reliability and mechanism of action of CSCs in cardiac disease therapy.
Understanding the exact mechanisms of how soluble factors from each SC type improves cardiac function is needed. This could lead to replacement of cell based therapy to soluble factor therapy through the use of biomimetic polymers to utilise the regenerative abilities of the soluble factors (Menasché, 2014).
Continue next generation trials to determine underlying mechanisms of CSCs role in improving cardiac function and conducting further trials with additional patients to increase integrity of data.
Introduce biomaterials as tools to increase cell retention and mediate soluble factor controlled release once transplanted to optimise SCc regeneration capabilities.
The initial belief that the mechanism of action was grafted SCs generated neomyocardium has been altered to one in which an endogenous repair mechanism based on paracrine factors derived from the SCs brings about the cardiac improvements. The cell type used has changed from non-cardiac to cardiac committed (CSCs) which contain specific soluble factors capable of cardiac regeneration. Optimising SC delivery to ensure cell grafting long enough to exhibit their paracrine effect is still a significant barrier. As understanding of cardiac regeneration increase, more specialisation of SC therapy for specific cardiac diseases will occur.
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