Stem cell therapy for muscular dystrophies

Abstract

Muscular dystrophies are a heterogeneous group of genetic diseases, characterized by progressive degeneration of skeletal and cardiac muscle. Despite the intense investigation of different therapeutic options, a definitive treatment has not been developed for this debilitating class of pathologies. Cell-based therapies in muscular dystrophies have been pursued experimentally for the last three decades. Several cell types with different characteristics and tissues of origin, including myogenic stem and progenitor cells, stromal cells, and pluripotent stem cells, have been investigated over the years and have recently entered in the clinical arena with mixed results. In this Review, we do a roundup of the past attempts and describe the updated status of cell-based therapies aimed at counteracting the skeletal and cardiac myopathy present in dystrophic patients. We present current challenges, summarize recent progress, and make recommendations for future research and clinical trials.

Figure 1. Overview of candidate cell types for cell therapy in muscular dystrophies.

Different types of progenitor cells derived from skeletal muscle or from nonmuscle tissues have been tested preclinically or clinically for therapeutic cell transplantation in muscular dystrophies. The identity of the progenitor cells and their tissue of origin are indicated. MSCs, mesenchymal stem cells; iPSCs, induced pluripotent stem cells; ESCs, embryonic stem cells; BMCs, bone marrow–derived cells.

Figure 2. Preservation of potency during in vitro culturing of myogenic cells for cell therapy applications.

(A) Expansion of MuSCs isolated from enzymatically digested skeletal muscles under standard culturing conditions on plastic dishes (upper path) selects for myoblasts with poor regenerative and engraftment capability. Two main strategies have been proposed to preserve the in vivo regenerative potential of MuSCs during in vitro culturing and resulted in productive engraftment in preclinical studies. One strategy (middle path) consists of the manipulation of artificial culturing substrates with bioengineering techniques to mimic the niche in which MuSCs reside and stimulate quiescence. The second strategy (lower path) consists of the adoption of culturing conditions favoring the expansion of myogenic progenitors with preserved regenerative potential. (B) Expansion of myogenic progenitors with preserved regenerative potential can be achieved through the addition to the culture medium of factors able to modulate the activity of fundamental signaling pathways, such as the Notch, JAK/STAT, oncostatin M (Osm), and p38 MAPK signaling pathways (, –140, 142); Setd7-dependent epigenetic modifications (143); eIF2α-dependent translational control (141); or the genetic alteration of regulators of myogenic lineage progression and proliferation.

Figure 3. Strategies aimed at increasing in vivo engraftment of transplanted cells.

(A–C) Approaches to enhance productive engraftment in cell transplantation experiments include targeting the cells to be transplanted and priming the recipient tissue. Productive engraftment is schematized by a transverse section of a transplanted muscle showing an increased proportion of fibers replenished by the transplanted cells (marked as blue fibers) compared with “No treatment condition,” as well as a reduction in the dystrophic pathology.