Indian Journal of Medical Research

CORRESPONDENCE
Year
: 2016  |  Volume : 143  |  Issue : 6  |  Page : 830--832

National multicentric M13 Stem Cell Trial reports negative outcome - Need to look at VSELs as an alternative to bone marrow MNCs for cardiac regeneration


Deepa Bhartiya 
 Stem Cell Biology Department, National Institute for Research in Reproductive Health (ICMR), Jehangir Merwanji Street, Parel, Mumbai 400 012, Maharashtra, India

Correspondence Address:
Deepa Bhartiya
Stem Cell Biology Department, National Institute for Research in Reproductive Health (ICMR), Jehangir Merwanji Street, Parel, Mumbai 400 012, Maharashtra
India




How to cite this article:
Bhartiya D. National multicentric M13 Stem Cell Trial reports negative outcome - Need to look at VSELs as an alternative to bone marrow MNCs for cardiac regeneration.Indian J Med Res 2016;143:830-832


How to cite this URL:
Bhartiya D. National multicentric M13 Stem Cell Trial reports negative outcome - Need to look at VSELs as an alternative to bone marrow MNCs for cardiac regeneration. Indian J Med Res [serial online] 2016 [cited 2019 Jul 15 ];143:830-832
Available from: http://www.ijmr.org.in/text.asp?2016/143/6/830/192080


Full Text

Sir,

I read with great interest the article by Nair et al[1] on a multicentric autologous stem cell trial for patients with acute myocardial infarction (AMI). This was undertaken on the basis of promising results in a pilot ABCD (Autologous Bone marrow Cells in Dilated cardiomyopathy) study reported from All India Institute of Medical Sciences (AIIMS), New Delhi [2] . Though the outcome is negative, it is important for the scientific community as well as the public to be aware of it. The results were not surprising as similar outcome was reported by other groups also [3] . I was disappointed by the discussion which was expected to comprehend recent progress in the field since 2007, lessons learnt and the forward path for the translation of stem cells in the country. Notably, no published articles from 2013-2015 are cited except one of our paper published in 2013.

Simple logic for doing a pilot study is to gauge beneficial effect (if any) of a new concept and if no striking beneficial effect is observed, one should give up on the idea and look at alternative options rather than advocating or concluding by mentioning that similar study on larger number of patients is required. Stem Cell Programme at the National Institutes of Health (NIH), USA was recently closed down [4] , and James Anderson, Director of the NIH's Division of Programme Coordination, Planning, and Strategic Initiatives, which administered the Centre for Regenerative Medicine mentioned that the field has progressed very fast and we need to brainstorm on how to move ahead. "To me that's just smart science," he said. "If something is not on track you don't keep spending money on it". The existing chaos and doubts in the field of stem cell therapy for the heart were discussed [5] . Nowbar et al[6] have recently compiled various discrepancies in autologous bone marrow (BM) stem cell trials and concluded that the effect of BM stem cell therapy on ejection fraction is zero.

As mentioned in the introduction of the article [1] , the transplanted mononuclear cells may exert a paracrine effect, engraft and integrate with host myocardium to bring about regeneration, may help remodel extracellular matrix or improve neo-vascularization or recruit endogenous stem cells. There is some clarity on this now since 2007 when the present clinical trial was initiated by Nair et al[1] . Firstly, we need to accept the fact that bone marrow transplantation (BMT) has been successful over decades to cure haematological disorders and is a standard method of care because BM mononuclear cells harbour a sub-population of haematopoietic stem cells (HSCs) which are already committed to haematological fate and thus can regenerate and cure blood disorders [7] . Hoping that the same HSCs can trans-differentiate into cardiac or endothelial cells is probably not true. Expecting the transplanted BM mononuclear cells (MNCs) to exert a paracrine effect (rich source of growth factors and cytokines) may also not hold. Cells in the BM that may be a rich source of growth factors and cytokines are evidently the mesenchymal cells. If we are hoping that a paracrine action can regenerate a damaged cardiac infarct, it will be best to expand mesenchymal stem cells (MSCs) in culture for transplantation rather than concluding that we need to conduct similar study of transplanting BM MNCs (which contain very few MSCs) on larger number of patients. It may be possible that MSCs could differentiate into cardiac cells and integrate with host myocardium as suggested by the authors since both MSCs and cardiac cells are mesodermal in origin. But this needs to be demonstrated in vitro first. van Berlo et al[8] have shown using lineage tracing studies that c-Kit positive cardiac stem cells in the heart do not differentiate into cardiomyocytes but this is still disputed [9] . Various groups have reviewed different kinds of stem cells and their potential for cardiac regeneration [10],[11] . It becomes extremely crucial to select the best stem cell candidate in the clinical settings.

BMT in both male and female patients who undergo very aggressive oncotherapy and conditioning regimen often is accompanied with spontaneous pregnancies and live births [12] . It was postulated that possibly the BM is a source of germ cells [13] . Thus a study was undertaken wherein mice were treated with cyclophosphamide to ablate the gonads and later green fluorescent protein (GFP) labelled BM MNCs were transplanted. However, all the pups born were non-GFP [14] and belonged to the recipient germline.

Research being carried out in a handful of laboratories across the world including our laboratory suggests that the ideal stem cells for regenerative medicine are possibly the primitive and pluripotent endogenous stem cells termed the very small embryonic-like stem cells (VSELs) existing in various adult organs (including the heart) throughout life and give rise to tissue specific progenitor stem cells which further proliferate and differentiate to maintain homeostasis [15] . More clarity is needed to define stem cells and distinguish them from the progenitors in the body organs [16] . VSELs survive oncotherapy in mammalian testis [17] , ovary [18] and also in the BM [19] and could possibly result in spontaneous pregnancies. Regenerative potential of VSELs has been reported in mice for lung epithelium [20] ; cardiac tissue [21],[22] ; neurons [23] ; pancreas [24],[25] ; liver [26] ; and in humans for critical limb ischaemia [27] ; cardiac tissue [28],[29] ; and diabetes [30] .

It is not clear as to why Nair et al[1] did not use VSELs rather than bone marrow MNCs. Miyanishi et al[31] were unable to detect VSELs by flow cytometry despite using published protocols and the same equipment. It was Ratajczak's group which successfully characterized these stem cells and reported that the VSELs were equivalent to primordial germ cells (PGCs) [15] . Rather than migrating to the gonads during early development, PGCs possibly migrate and settle in all developing organs and persist throughout life as VSELs [15] .

The reason why VSELs have remained elusive till date is their very small size and rare occurrence and these get unknowingly discarded while processing cells for various experiments. Density gradient centrifugation method is the standard method to isolate stem cells (from bone marrow or peripheral blood) wherein the mononuclear cells (MNCs) are enriched in the 'buffy coat' and the red blood cells at the bottom are discarded. However, it was found that VSELs invariably settle down with the RBCs [32],[33] and thus have never been extensively studied.

It will be ideal for Nair et al[1] to modify their isolation protocols to include VSELs (for regeneration) and MSCs (as a source of growth factors and cytokines) in their trials in future rather than transplanting MNCs in more number of patients. HSCs do not trans-differentiate and regenerate the cardiac tissue. Moreover, injecting the stem cells into the margins of the infracted heart may be a better option than transplanting cells through coronary artery.

Conflicts of Interest: None.

References

1Nair V, Madan H, Sofat S, Ganguli P, Jacob MJ, Datta R, et al; for M13 Trial Efficacy of stem cell in improvement of left ventricular function in acute myocardial infarction - MI3 Trial. Indian J Med Res 2015; 142 : 165-74.
2Seth S, Narang R, Bhargava B, Ray R, Mohanty S, Gulati G, et al; AIIMS Cardiovascular Stem Cell Study Group. Percutaneous intracoronary cellular cardiomyoplasty for nonischemic cardiomyopathy: clinical and histopathological results: the first-in-man ABCD (Autologous Bone Marrow Cells in Dilated Cardiomyopathy) trial. J Am Coll Cardiol 2006; 48 : 2350-1.
3Wang X, Zhang J, Zhang F, Li J, Li Y, Tan Z, et al. The clinical status of stem cell therapy for ischemic cardiomyopathy. Stem Cells Int 2015; 2015 : article ID 135023 (13 pages).
4Reardon S. NIH stem-cell programme closes. Nature 2014; 508 : 157.
5Abbott A. Doubts over heart stem-cell therapy. Nature 2014; 509 : 15-6.
6Nowbar AN, Mielewczik M, Karavassilis M, Dehbi HM, Shun-Shin MJ, Jones S, et al. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ 2014; 348 : g2688.
7Hematopoietic Stem Cells. In: Stem cell information. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services; 2011. Available from: http://stemcells.nih.gov/info/scireport/pages/chapter5.aspx, accessed on June 28, 2016.
8van Berlo JH, Kanisicak O, Maillet M, Vagnozzi RJ, Karch J, Lin SC, et al. c-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 2014; 509 : 337-41.
9Nadal-Ginard B, Ellison GM, Torella D. Absence of evidence is not evidence of absence: pitfalls of cre knock-ins in the c-Kit locus. Circ Res 2014; 115 : 415-8.
10Dixit P, Katare R. Challenges in identifying the best source of stem cells for cardiac regeneration therapy. Stem Cell Res Ther 2015; 6 : 26.
11Ratajczak MZ, Jadczyk T, Pêdziwiatr D, Wojakowski W. New advances in stem cell research: Practical implications for regenerative medicine. Pol Arch Med Wewn 2014; 124 : 417-26.
12Salooja N, Szydlo RM, Socie G, Rio B, Chatterjee R, Ljungman P, et al. Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. Lancet 2001; 358 : 271-6.
13Du H, Taylor HS. Stem cells and reproduction. Curr Opin Obstet Gynecol 2010; 22 : 235-41.
14Lee HJ, Selesniemi K, Niikura Y, Niikura T, Klein R, Dombkowski DM, et al. Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol 2007; 25 : 3198-204.
15Ratajczak MZ. A novel view of the adult bone marrow stem cell hierarchy and stem cell trafficking. Leukemia 2015; 29 : 776-82.
16Bhartiya D. Stem cells, progenitors & regenerative medicine: A retrospection. Indian J Med Res 2015; 141 : 154-61.
17Anand S, Patel H, Bhartiya D. Chemoablated mouse seminiferous tubular cells enriched for very small embryonic-like stem cells undergo spontaneous spermatogenesis in vitro. Reprod Biol Endocrinol 2015; 13 : 33.
18Sriraman K, Bhartiya D, Anand S, Bhutda S. Mouse ovarian very small embryonic-like stem cells resist chemotherapy and retain ability to initiate oocyte-specific differentiation. Reprod Sci 2015; 22 : 884-903.
19Shaikh A, Bhartiya D, Kapoor S, Nimkar H. Delineating the effects of 5-fluorouracil and follicle-stimulating hormone on mouse bone marrow stem/progenitor cells. Stem Cell Res Ther 2016; 7 : 59-74.
20Kassmer SH, Jin H, Zhang PX, Bruscia EM, Heydari K, Lee JH, et al. Very small embryonic-like stem cells from the murine bone marrow differentiate into epithelial cells of the lung. Stem Cells 2013; 31 : 2759-66.
21Dawn B, Tiwari S, Kucia MJ, Zuba-Surma EK, Guo Y, Sanganalmath SK, et al. Transplantation of bone marrow-derived very small embryonic-like stem cells attenuates left ventricular dyfunction and remodeling after myocardial infarction. Stem Cells 2008; 26 : 1646-55.
22Zuba-Surma EK, Kucia M, Dawn B, Guo Y, Ratajczak MZ, Bolli R. Bone marrow-derived pluripotent very small embryonic-like stem cells (VSELs) are mobilized after acute myocardial infarction. J Mol Cell Cardiol 2008; 44 : 865-73.
23Grymula K, Tarnowski M, Piotrowska K, Suszynska M, Mierzejewska K, Borkowska S, et al. Evidence that the population of quiescent bone marrow-residing very small embryonic/epiblast-like stem cells (VSELs) expands in response to neurotoxic treatment. J Cell Mol Med 2014; 18 : 1797-806.
24Bhartiya D, Mundekar A, Mahale V, Patel H. Very small embryonic-like stem cells are involved in regeneration of mouse pancreas post-pancreatectomy. Stem Cell Res Ther 2014; 5 : 106.
25Bhartiya D, Patel H. Very small embryonic-like stem cells are involved in pancreatic regeneration and their dysfunction with age may lead to diabetes and cancer. Stem Cell Res Ther 2015; 6 : 96.
26Chen ZH, Lv X, Dai H, Liu C, Lou D, Chen R, et al. Hepatic regenerative potential of mouse bone marrow very small embryonic-like stem cells. J Cell Physiol 2015; 230 : 1852-61.
27Guerin CL, Loyer X, Vilar J, Cras A, Mirault T, Gaussem P, et al. Bone-marrow-derived very small embryonic-like stem cells in patients with critical leg ischaemia: evidence of vasculogenic potential. Thromb Haemost 2015; 113 : 1084-94.
28Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Paczkowska E, Ciosek J, et al. Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. J Am Coll Cardiol 2009; 53 : 1-9.
29Wojakowski W, Tendera M, Kucia M, Zuba-Surma E, Milewski K, Wallace-Bradley D, et al. Cardiomyocyte differentiation of bone marrow-derived Oct-4+CXCR4+SSEA-1+ very smallembryonic-like stem cells. Int J Oncol 2010; 37 : 237-47.
30Abouzaripour M, Ragerdi Kashani I, Pasbakhsh P, Atlasy N. Intravenous transplantation of very small embryonic like stem cells in treatment of diabetes mellitus. Avicenna J Med Biotechnol 2015; 7 : 22-31.
31Miyanishi M, Mori Y, Seita J, Chen J, Karten S, Chan CK, et al. Do pluripotent stem cells exist in adult mice as very small embryonic stem cells? Stem Cell Rep 2013; 1 : 198-208.
32Shaikh A, Nagvenkar P, Pethe P, Hinduja I, Bhartiya D. Molecular and phenotypic characterization of CD133 and SSEA4 enriched very small embryonic-like stem cells in human cord blood. Leukemia 2015; 29 : 1909-17.
33Bhartiya D, Shaikh A, Nagvenkar P, Kasiviswanathan S, Pethe P, Pawani H, et al. Very small embryonic-like stem cells with maximum regenerative potential get discarded during cord blood banking and bone marrow processing for autologous stem cell therapy. Stem Cells Dev 2012; 21 : 1-6.