Repeated Cell Therapy

Abstract

Although treatment with stem/progenitor cells is a promising approach to heart disease, enthusiasm for cell therapy has been dampened by the inconsistent, modest, borderline, or undetectable benefits reported in clinical trials (all of which have used 1 dose of cells).1–4 As a result, clinical translation has not occurred (no cell-based therapy is close to being approved for heart disease), and a rising tide of skepticism has bedeviled the field,5,6 leading some critics even to question whether clinical studies should continue. Here, I propose that a major reason for the modest, borderline, or disappointing results is the administration of only 1 dose of cells, which causes the benefits of cell therapy to be underestimated. I argue that just as most pharmacological agents are ineffective when given once but can be highly effective when given repeatedly, so a cell product may be ineffective, or modestly effective, when given as a single treatment, but may turn out to be quite efficacious if given repeatedly. This concept constitutes a major paradigm shift (a “game changer”), with potentially vast implications for the entire field of reparative medicine.The efficacy of cell therapy is limited by the poor engraftment of the cells, which disappear rapidly after transplantation. For example, after administration of c-kitPOS cardiac progenitor cells (CPCs) in mice, rats, and pigs, the number of cells remaining in the heart declines precipitously to very low values1,2,7,8; in the mouse heart, <8% of the CPCs present immediately after transplantation remain 1 week later, and after 35 days this number falls to <3%.8 Despite this, administration of CPCs improves left ventricular (LV) function, and the improvement is long lasting (at least 1 year).1,2,7,8 Rapid disappearance of transplanted cells …