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.

Adiponectin as a tissue regenerating hormone: more than a metabolic function

“…Among non-resident precursors, a variety of different cells with intrinsic myogenic properties have been isolated. These include adipose-tissue derived stem cells [47], mesoangioblasts [48], pericytes [49], muscle-derived stem cells [50], side-population cells [51][52][53], Ac133 + cells [54], stem and/or precursor cells from muscle endothelium [55], and synovium [56]. Mesoangioblasts, multipotent progenitors of mesodermal tissues, particularly attracted scientific attention for their possible use in stem cell therapy since they ameliorated some myopathies in animal models.…”

Simultaneous characterization of progenitor cell compartments in adult human liver

“…The analyses of all staining tubes were performed on viable cells (not stained with 7-AAD) with a scatter profile typical of stem/progenitor cells: i.e. intermediate/high FSC and low/intermediate SSC (10,12,14). Viable MNLCs were then divided into CD45 1 and CD45 2 cells.…”

“…As a result, FCM has become the gold standard to characterize clinical grade cell preparations in several fields of regenerative medicine. In our own laboratories, it has allowed the identification of rare stem cells and progenitors in peripheral blood and parenchymal tissues (12)(13)(14), thus prompting us to refine FCM protocols for liver stem cell analysis with a view to future clinical applications.…”

Muscle stem cells and model systems for their investigation

“…For all these reasons, the attention has turned to other sources of donor cells and in particular the embryonic vasculature-derived mesoangioblasts (De Angelis et al, 1999;Minasi et al, 2002;Galvez et al, 2006), their adult counterparts, the pericytes (Dellavalle et al, 2007), as well as the circulating AC133ϩ cells (Torrente et al, 2004) that appear to be the most promising candidates. The mesoangioblasts were found to repopulate and to repair diseased skeletal muscles in dystrophic mice and also in dystrophic golden retriever dogs, which represent a faithful model of human DMD .…”

“…Moreover, a subpopulation of bloodderived circulating cells expressing a well-characterized hematopoietic marker AC133 (Torrente et al, 2004) were found to undergo myogenic differentiation in vitro (in co-culture with myogenic cells) or in vivo when delivered into the muscles of transgenic scid/mdx mice. After treatment, some injected AC133ϩ cells localized under the basal lamina of host muscle fibers and expressed satellite cell markers such as M-cadherin and Myf5.…”