Relative Roles of CD90 and c‐Kit to the Regenerative Efficacy of Cardiosphere‐Derived Cells in Humans and in a Mouse Model of Myocardial Infarction

Abstract

BackgroundThe regenerative potential of cardiosphere‐derived cells (CDCs) for ischemic heart disease has been demonstrated in mice, rats, pigs, and a recently completed clinical trial (CADUCEUS). CDCs are CD105+ stromal cells of intrinsic cardiac origin, but the antigenic characteristics of the active fraction remain to be defined. CDCs contain a small minority of c‐kit+ cells, which have been argued to be cardiac progenitors, and a variable fraction of CD90+ cells whose bioactivity is unclear.MethodsWe performed a retrospective analysis of data from the CADUCEUS trial and a prospective mouse study to elucidate the roles of c‐kit+ and CD90+ cells in human CDCs. Here, we show, surprisingly, that c‐kit expression has no relationship to CDCs' therapeutic efficacy in humans, and depletion of c‐kit+ cells does not undermine the structural and functional benefits of CDCs in a mouse model of myocardial infarction (MI). In contrast, CD90 expression negatively correlates with the therapeutic benefit of CDCs in humans (ie, higher CD90 expression associated with lower efficacy). Depletion of CD90+ cells augments the functional potency of CDCs in murine MI. CD90− CDCs secrete lower levels of inflammatory cytokines and can differentiate into cardiomyocytes in vitro and in vivo.ConclusionThe majority population of CDCs (CD105+/CD90−/c‐kit−) constitutes the active fraction, both in terms of therapeutic efficacy and in the ability to undergo cardiomyogenic differentiation. The c‐kit+ fraction is neither necessary for, nor contributory to, the regenerative efficacy of CDCs.

Meta-Analysis of Cell Therapy Trials for Patients With Heart Failure

“…Although the limitations of cell delivery and cell engraftment have been recognized before, 69 cells may not be needed to engraft long-term although still exerting their long-lasting therapeutic benefit. 70 In conclusion, we show that cell therapies may have a clinical benefit for patients with HF, as they seem to significantly reduce mortality and rehospitalization in the long-term. Although promising, these results need to be confirmed in larger appropriately randomized clinical trials in which both clinicans and participants are blinded.…”

Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells

“…cells isolated from diabetic patients (70), and it is important because CD90 positivity is associated with lower therapeutic efficacy in myocardial cell therapy (70,71). It remains unclear how diabetes increases CD90 positivity in the CPC population or whether its expression contributes to altered metabolic pathways in hyperglycemic conditions.…”

Cardiac Regeneration and Stem Cells

“…While cardiospheres contain a rare cardiac progenitor population that has limited cardiac myocyte differentiation potential (29), their therapeutic benefit in vivo is likely independent of this progenitor cell and has been proposed to be secondary to stimulating endogenous repair mechanisms including new myogenesis (59,65). Although the active cell in cardiospheres is unknown, CD90-negative population tended to perform better in terms of cardiac differentiation potential and therapeutic benefit in injured hearts (19,29). The first phase I trial in humans using cardiospheres, CADUCEUS, did not demonstrate a significant difference in LV ejection fraction or volumes between groups; however, compared with the control group, CDC-treated patients showed an increase in viable myocardium and reductions in scar mass at the 6-month time point (64).…”