Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle

Abstract

Duchenne muscular dystrophy (DMD) is a common X-linked disease characterized by widespread muscle damage that invariably leads to paralysis and death.There is currently no therapy for this disease.Here we report that a subpopulation of circulating cells expressing AC133, a well-characterized marker of hematopoietic stem cells, also expresses early myogenic markers.Freshly isolated, circulating AC133 + cells were induced to undergo myogenesis when cocultured with myogenic cells or exposed to Wnt-producing cells in vitro and when delivered in vivo through the arterial circulation or directly into the muscles of transgenic scid/mdx mice (which allow survival of human cells).Injected cells also localized under the basal lamina of host muscle fibers and expressed satellite cell markers such as M-cadherin and MYF5.Furthermore, functional tests of injected muscles revealed a substantial recovery of force after treatment.As these cells can be isolated from the blood, manipulated in vitro, and delivered through the circulation, they represent a possible tool for future cell therapy applications in DMD disease or other muscular dystrophies.Nonstandard abbreviations used: CFU in culture (CFU-C); control (CTR); crosssectional area (CSA); differentiation medium (DM); Duchenne muscular dystrophy (DMD); enhanced GFP (eGFP); force (Po); gastrocnemius (Gas); human dystrophin (Dys3); Iscove's modified Dulbecco's medium (IMDM); muscle-derived stem cell (MDSC); myosin heavy chain (MyHC); phycoerythrin (PE); proliferation medium (PM); quadriceps (Qd); sarcomere length (SL); soleus (Sol); stem cell factor (SCF); telomere repeat-amplification protocol (TRAP); tibialis anterior (TA); treated (TR).