Stem cell-derived therapeutic myelin repair requires 7% cell replacement.
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 (T(50) > 128 days) relative to both shiverer (T(50) = 108 days) and the nonrescued chimeras. Retrospective genotype analysis identified a strong correlation (r(2) = 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.
Kiel
Mary E
ME
UMDNJ-Robert Wood Johnson Medical School, 675 Hoes Lane, S-225, Piscataway NJ 08854, USA.
Chen
Cui P
CP
Sadowski
Dorota
D
McKinnon
Randall D
RD
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002678:Chimera; D053595:Embryonic Stem Cells / Q000166:cytology / Q000637:transplantation*; D008136:Longevity; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity; D004676:Myelin Basic Protein / Q000096:biosynthesis* / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics / Q000502:physiology*; D012038:Regeneration
D004676:Myelin Basic Protein