Stem Cell-Derived Therapeutic Myelin Repair Requires 7% Cell Replacement

Abstract

Abstract Embryonic stem cells (ESCs) hold great potential for therapeutic regeneration and repair in many diseases. However, many challenges remain before this can be translated into effective therapy. A principal and significant limit for outcome evaluations of clinical trials is to define the minimal graft population necessary for functional repair. Here we used a preclinical model for quantitative analysis of stem cell grafts, with wild-type ESC grafted into myelin mutant shiverer hosts, to determine minimum graft levels for therapeutic benefit. Using a timed motor function test we identified three groups, including recipients indistinguishable from nongrafted shiverer controls (time [t] = 20.1 ± 1.1 seconds), mice with marginal improvement (t = 15.7 ± 1 seconds), and mice with substantial phenotype rescue (t = 5.7 ± 0.9 seconds). The motor function rescued chimeras also had a considerably extended life span (T50 > 128 days) relative to both shiverer (T50 = 108 days) and the nonrescued chimeras. Retrospective genotype analysis identified a strong correlation (r2 = 0.85) between motor function and ESC-derived chimerism, with > 7% chimerism required for rescue in this murine model of central nervous system myelin pathology. These results establish the minimal levels of engraftment to anticipate therapeutic repair of a cell-autonomous defect by cell transplant therapy. Disclosure of potential conflicts of interest is found at the end of this article.