Journal of Molecular and Cellular Cardiology 42 (2007) 727–729www.elsevier.com/locate/yjmcc

Editorial

Cord blood and myocardial infarction: An uncertain wedding

In the ongoing quest for the ideal cell type featuring thegreatest potential of cardiac regeneration, cord blood cells arecurrently raising a growing interest for two major reasons. First,they contain stem and progenitor cells with an attractive

proliferative and multilineage differentiation potential. Second,they can be easily collected noninvasively, expanded and cold-stored, thereby providing an “off-the-shelf” product readilyavailable in an emergency setting. Their routine use as analternative to bone marrow transplantation in patients affectedby hematological diseases further strengthens the clinicalrelevance of their potential application for regenerative therapy.Indeed, the excitement is such that private companies are yetaggressively advertising cord blood cell banking for nonhema-tological use and, based on lay press reports, top-rank soccerplayers have already applied, among others, for having stemcells from their children's umbilical cords frozen in these banksin the perspective of future tissue repair!

Far away from this overhype, the study by Moelker andcoworkers [1] tends to dampen this enthusiastic view. Using aswine model of reperfused myocardial infarction, these authorshave injected 100 million of cord blood cells directly into theinfarct-related coronary artery 1 week later, thereby closelymimicking the clinical scenario of current bone marrow celltransplantation trials. Magnetic resonance imaging (MRI) wasthen used for assessing the outcomes after 4 weeks. Not only didcord blood cell treatment failed to improve regional or globalleft ventricular function compared with saline-infused controls,but it also even resulted in more extensive infarcts with a greaterdegree of inflammatory cell infiltration and calcifications.These carefully collected and analyzed data call for three majorobservations.

The first is that cord blood cells, despite their purportedplasticity, are apparently unable to convert into cardiomyocytesin the in vivo setting of an infarcted myocardial tissue. In aprevious study, Hirata and coworkers [2] had already shown in arat model of permanent coronary artery occlusion that cordblood derived-CD34+ progenitors could only adopt thephenotype of smooth muscle cells, as evidenced by immunos-taining of the engrafted cells by human-specific α-smoothmuscle actin. In a closely related model, Ma and colleagues [3]have also failed to document any conversion of intravenouslyinjected cord blood cells into cardiomyocytes and only some ofthose which had homed into infarcted areas displayed anendothelial-cell like phenotype. Likewise, in the study by Leor

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et al. [4], the cord blood-derived CD133+ cells identified in themyocardium following a femoral vein infusion mostly differ-entiated along the hematopoietic lineage. Taking a similarlyselective approach, Moelker and colleagues [1] have not usedthe bulk of cord blood cells but rather a purified population of“unrestricted somatic stem cells”, a CD-45-negative fractionreported to be pluripotent and highly proliferative (it can beexpanded up to 1015 cells while maintaining a normal kariotype[5]). So far, however, the differentiation of this cell populationalong the cardiomyocytic pathways has only been documentedin the preimmune fetal sheep model [5] and it does not seem tooccur under the more clinically relevant conditions ofpostinfarction cell transplantation. Indeed, the finding of in-scar calcifications in the cord blood cell-infused group ofMoelker's experiments reminds what has been previouslyreported with mesenchymal stem cells [6] which are thought torepresent a later developmental stage of unrestricted somaticstem cells. This finding does not refute the concept that thesecells have a plasticity potential but suggests that following theirengraftment in infarcted tissue, they may respond to local cuesby rather differentiating along a chondrogenic/osteogenicpathway. This assumption is consistent with the recent reportthat cells of the mesodermal lineage are sensitive to the physicalproperties of the supporting extracellular matrix and that thestiffer the matrix, the greater the likelihood of an chondrogenic/osteogenic differentiation [7]. Importantly, previous studies ofcord blood cell transplantation in rat models of myocardialinfarction [2–4,8] suggest that the lack of conversion of thetransplanted cells into cardiomyocytes does not preclude animprovement in left ventricular function. Such a discrepancy isusually explained by a paracrine effect of the graft leading toincreased angiogenesis [2,3], changes in extracellular matrixcomposition reducing collagen content [3] or recruitment ofendogenous myofibroblasts cells leading to increase scarthickness with an attendant reduction of paradoxical systolicbulging and an improvement in left ventricular function [4].However, in the present experiments, the use of what is usuallyconsidered the currently most accurate tool for assessing leftventricular function and geometry, i.e., MRI, failed to documentsuch an improvement.

Thus the second observation drawn from Moelker's experi-ments pertains to the lack of functional efficacy of theintracoronarily infused cord blood-derived unrestricted somaticstem cells. This finding is puzzling in view of the opposite

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conclusion made by Kim and colleagues [9] following the useof the same cell population at a similar dosage. However, someimportant differences in the experimental protocols mayaccount for these seemingly divergent results.

Although the two studies were conducted in a swine model,the Moelker's experiments have entailed early (1 week) cellinfusion in a reperfused infarct whereas in those of Kim et al.[9], cell transfer was delayed until 4 weeks in a nonreperfusedscar. Notwithstanding the expected differences in the extent oftissue healing and the nature of local signaling pathways, theformer protocol mimics the early implementation of cell therapyin patients with acutely revascularized infarctions whereas thelatter rather addresses the chronic setting of patients with heartfailure. However, the most important difference between thetwo studies is probably the route for cell delivery. In line withthe simulated clinical indication, Moelker et al. infused cellspercutaneously into the infarct-related coronary artery whereasKim et al. [9] used an open-chest approach for injecting themdirectly into the scar tissue. Unrestricted somatic stem cells havea size of approximately 20–25 μm, which is twice larger thanbone marrow-derived mononuclear cells. It is therefore notunexpected that intraarterial infusion of these bulky cells led todistal capillary plugging which most likely accounts for themore extensive infarcts seen in the treated group and the relatedlack of functional benefits. This finding has important practicalimplications in that it implies that the clinical use ofintracoronarily delivered unrestricted somatic stem cellswould raise a major safety concern. As, at the acute stage ofmyocardial infarction, only percutaneous approaches can bereasonably used for cell transfer, alternate routes have to beconsidered. In this setting, endoventricular injections may lookattractive but many cardiologists would probably be reluctant topuncture a freshly infarcted endocardium. The trans-coronarysinus route is another option but may be plagued with technicaldifficulties. Finally, homing of intravenously injected cells toinfarcted areas through a SDF-1-CXCR4-mediated pathway hasbeen documented in murine models [3,4] but still remainselusive in man [10]. Put together, these data suggest thatalthough unrestricted somatic stem cells could probably besafely injected in patients with chronic scars, their practical useduring the early postinfarct period appears much moreproblematic. Clearly, this statement does not apply to cordblood-derived mononuclear cells or CD34+/CD133+ progeni-tors whose smaller size is compatible with an intraarterialinfusion. The question is then to determine the benefit of suchpopulations compared to the same ones retrieved from thepatient's own bone marrow. The proponents of cord blood willthen argue that the major advantage of cord blood overautologous marrow is to provide a banked, readily availableproduct which, despite its allogeneic nature, is not immuno-genic. This assumption is seriously challenged by the thirdobservation drawn from Moelker's experiments.

Although, in one study [8], human cord blood cells havebeen injected into rat hearts and apparently tolerated withoutimmunosuppression, other protocols conducted in murinemodels have entailed use of either immunoincompetent animals[3,4] or an immunosuppressive regimen (2). Indeed, the concept

of an immune privilege of cord blood cells is largely based onthe finding that its cultured unrestricted somatic stem cellcompartment is negative for Human Leukocyte Antigen (HLA)-class II molecules and weakly expresses class I antigens [5].This, however, does not exclude the immunogenicity of thedifferentiated derivatives of these cells, as described withembryonic stem cells [11]. Although Moelker reports similarhistological patterns of inflammatory cell infiltration in swinesacrificed 4 days after infarction, regardless of whetherimmunosuppression was given or not, this early timing ofassessment precludes definite conclusions and, indeed, CD3-positive cells were identified despite a continuous ciclosporinetreatment in animals studied at a later time point, i.e., 4 weeksafter unrestricted somatic stem cell transplantation. Thepresence of immune cells was similarly detected in the studyof Kim et al [9] who also used a ciclosporine-basedimmunosuppression. Using bioluminescence imaging, Min etal. [12] have also showed that survival of intramyocardiallyinjected cord blood-derived mesenchymal stem cells wassignificantly greater in rats receiving either tacrolimus orciclosporine compared with untreated controls. Put together,these data raise a cautionary note about the immune privilege ofcord blood cells and additional studies are clearly warranted toassess whether this attractive characteristic is a wishful thinkingor a convincingly demonstrated scientific reality.

In summary, the study of Moelker and associates is importantfor at least three major reasons : (1) the care with which theexperiments have been designed and conducted, (2) the clinicalrelevance of the protocol and (3) the practical implications ofthe conclusions. Clearly, intracoronary infusion of unrestrictedsomatic stem cells in patients with a recent myocardialinfarction would be neither safe nor functionally effective.This does not rule out a possible role of cord blood cells used inmore chronic settings but emphasizes that important issues stillneed to be addressed, particularly the characterization of thefunctionally relevant cell fraction in relation with the therapeu-tic objective (paracrine signaling versus structural regenera-tion), the optimal route for cell delivery and the conditions ofenhanced immune tolerance of the host to the cellular graft.Last, but not least, the authors should be complimented forreporting the negative outcome of their trial as, in thisburgeoning field of cell therapy where different cell types areperiodically claimed to have an almost miraculous myocardialregeneration potential, the honest description of negativestudies, well conducted in clinically relevant large animalmodels, is of utmost importance for helping to move the fieldforward.

References

[1] Moelker AD, Baks T, Wever KMAM, Spitskovsky D, Wielopolski PA, vanBeusekom HMM, et al. Intracoronary delivery of umbilical cord bloodderived unrestricted somatic stem cells is not suitable to improve LVfunction after myocardial infarction in swine. J Mol Cell 2006.

[2] Hirata Y, Sata M, Motomura N, Takanashi M, Suematsu Y, Ono M,et al. Human umbilical cord blood cells improve cardiac function aftermyocardial infarction. Biochem Biophys Res Commun 2005;327:609–14.

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[3] Ma N, Stamm C, Kaminski A, Li W, Kleine HD, Muller-Hilke B, et al.Human cord blood cells induce angiogenesis following myocardialinfarction in NOD/scid-mice. Cardiovasc Res 2005;66:45–54.

[4] Leor J, Guetta E, Feinberg MS, Galski H, Bar I, Holbova R, et al. Humanumbilical cord blood-derived CD133+ cells enhance function and repair ofthe infarcted myocardium. Stem Cells 2006;24:772–80 [Erratum in: StemCells 2006;24:1627].

[5] Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N, et al. Anew human somatic stem cell from placental cord blood with intrinsicpluripotent differentiation potential. J Exp Med 2004;200:123–35.

[6] Yoon YS, Park JS, Tkebuchava T, Luedeman C, Losordo DW. Unexpectedsevere calcification after transplantation of bone marrow cells in acutemyocardial infarction. Circulation 2004;109:3154–7.

[7] Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stemcell lineage specification. Cell 2006;126:677–89.

[8] Henning RJ, Abu-Ali H, Balis JU, Morgan MB, Willing AE, Sanberg PR.Human umbilical cord blood mononuclear cells for the treatment of acutemyocardial infarction. Cell Transplant 2004;13:729–39.

[9] Kim BO, Tian H, Prasongsukarn K, Wu J, Angoulvant D, Wnendt S, et al.Cell transplantation improves ventricular function after a myocardialinfarction: a preclinical study of human unrestricted somatic stem cells in aporcine model. Circulation 2005;12(Suppl I):I96–104.

[10] HofmannM, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B,et al. Monitoring of bone marrow cell homing into the infarcted humanmyocardium. Circulation 2005;111:2198–202.

[11] Swijnenburg RJ, Tanaka M, Vogel H, Baker J, Kofidis T, Gunawan F, et al.Embryonic stem cell immunogenicity increases upon differentiation aftertransplantation into ischemic myocardium. Circulation 2005;112(Suppl I):I166–72.

[12] Min JJ, Ahn Y, Moon S, Kim YS, Park JE, Kim SM, et al. In vivobioluminescence imaging of cord blood derived mesenchymal stem celltransplantation into rat myocardium. Ann Nucl Med 2006;20:165–70.

Philippe MenaschéHôpitaux de Paris, Hôpital Européen Georges Pompidou,

Department of Cardiovascular Surgery,University Paris-Descartes, Faculte de Medecine,

INSERM U 633, Paris, FranceE-mail address: philippe.menasche@hop.egp.ap-hop-paris.fr.

8 February 2007