Paliwal Preeti, Conboy Irina M
Department of Bioengineering, University of California, Berkeley, CA 94720, USA.
Chem Biol. 2011 Sep 23;18(9):1153-66. doi: 10.1016/j.chembiol.2011.07.012.
Muscle regeneration declines with aging and myopathies, and reprogramming of differentiated muscle cells to their progenitors can serve as a robust source of therapeutic cells. Here, we used the Cre-Lox method to specifically label postmitotic primary multinucleated myotubes and then utilized small molecule inhibitors of tyrosine phosphatases and apoptosis to dedifferentiate these myotubes into proliferating myogenic cells, without gene overexpression. The reprogrammed, fusion competent, muscle precursor cells contributed to muscle regeneration in vitro and in vivo and were unequivocally distinguished from reactivated reserve cells because of the lineage marking method. The small molecule inhibitors downregulated cell cycle inhibitors and chromatin remodeling factors known to promote and maintain the cell fate of myotubes, facilitating cell fate reversal. Our findings enhance understanding of cell-fate determination and create novel therapeutic approaches for improved muscle repair.
肌肉再生能力会随着衰老和肌病而下降，将分化的肌肉细胞重编程为其祖细胞可作为一种强大的治疗细胞来源。在此，我们使用Cre-Lox方法特异性标记有丝分裂后的原代多核肌管，然后利用酪氨酸磷酸酶和凋亡的小分子抑制剂将这些肌管去分化为增殖性肌源性细胞，而无需基因过表达。重编程后的、具有融合能力的肌肉前体细胞在体外和体内都有助于肌肉再生，并且由于谱系标记方法，它们与重新激活的储备细胞有明确区分。小分子抑制剂下调了已知促进和维持肌管细胞命运的细胞周期抑制剂和染色质重塑因子，促进了细胞命运的逆转。我们的研究结果增进了对细胞命运决定的理解，并为改善肌肉修复创造了新的治疗方法。
