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 …