Fusion of bone marrow-derived stem cells with striated muscle may not be sufficient to activate muscle genes

Abstract

Several studies have demonstrated the existence of pluripotent bone marrow-derived stem cells capable of homing to injured cardiac and skeletal muscle; however, there has been little evidence demonstrating the induction of tissue-specific endogenous genes in donor stem cells following engraftment. A new study in this issue reports an intriguing finding that raises additional concerns relating to stem cell plasticity and stem cell therapy in an already heated and controversial field. The study demonstrates that wild-type bone marrow-derived side population stem cells are indeed readily incorporated into both skeletal and cardiac muscle when transplanted into mice that lack delta-sarcoglycan -- a model of cardiomyopathy and muscular dystrophy. However, these cells fail to express sarcoglycan and thus to repair the tissue, which suggests that this stem cell population has limited potential for cardiac and skeletal muscle regeneration.

Figure 1

Schematic representation of the dystroglycan complex at the membrane of the muscle cell. A number of transmembrane proteins, including dystroglycan (DG), sarcospan (SP), and sarcoglycans (α, β, γ, and δ), connect the actin cytoskeleton to the basal lamina by binding dystrophin (in turn linked to actin) on the cytoplasmic side and laminin on the extracellular side of the muscle plasma membrane. Other functionally important proteins such as nitric oxide synthetase (NOS) are maintained at the cytoplasmic side of the membrane by a different protein complex also bound to dystrophin.

Figure 2

Different degrees of reprogramming of the nucleus of a wild-type BM-SP stem cell from a male mouse once inside a cardiomyocyte or a myofiber of a female δ-sarcoglycan_null mouse. The model proposes that the Y chromosome_positive (green) donor nucleus (gray) will be exposed to transcription factors from recipient nuclei (cream) as a consequence of either fusion or transdifferentiation. The donor nucleus may then be subject to different fates: no reprogramming at all (I); transcription of myogenic determination genes but not of muscle structural genes (II); transcription of myogenic determination genes and of muscle structural genes expressed during early differentiation only (III); or transcription of all muscle genes (IV). The last event is ruled out in the study of Lapidos et al. (8) by the lack of δ-sarcoglycan expression observed after transplantation of wild-type BM-SP stem cells into δ-sarcoglycan_null mice.