Department of Orthopaedic Surgery, Washington University, St. Louis, MO, USA.
Center of Regenerative Medicine, Washington University, St. Louis, MO, USA.
FASEB J. 2020 Jul;34(7):9740-9754. doi: 10.1096/fj.202000330R. Epub 2020 Jun 7.
Humans have limited regenerative potential of musculoskeletal tissues following limb or digit loss. The murine digit has been used to study mammalian regeneration, where stem/progenitor cells (the "blastema") completely regenerate the digit tip after distal, but not proximal, amputation. However, the molecular mechanisms responsible for this response remain to be determined. Here, we evaluated the spatiotemporal formation of bone and fibrous tissues after level-dependent amputation of the murine terminal phalanx and quantified the transcriptome of the repair tissue. Distal (regenerative) and proximal (non-regenerative) amputations showed significant differences in temporal gene expression and tissue regrowth over time. Genes that direct skeletal system development and limb morphogenesis are transiently upregulated during blastema formation and differentiation, including distal Hox genes. Overall, our results suggest that digit tip regeneration is controlled by a gene regulatory network that recapitulates aspects of limb development, and that failure to activate this developmental program results in fibrotic wound healing.
人类在肢体或指/趾缺失后，其骨骼肌肉组织的再生能力有限。在研究哺乳动物再生的过程中，研究人员使用了鼠类的指/趾，在远端切除后，而不是近端切除后，指/趾尖端的干细胞/祖细胞（“芽基”）可以完全再生指/趾。然而，负责这种反应的分子机制仍有待确定。在这里，我们评估了在鼠类终末指节水平依赖性切除后，骨和纤维组织的时空形成，并对修复组织的转录组进行了定量分析。远端（再生）和近端（非再生）切除在时间上的基因表达和组织再生方面存在显著差异。在芽基形成和分化过程中，包括远端同源盒基因在内的骨骼系统发育和肢体形态发生的指导基因会短暂上调。总的来说，我们的研究结果表明，指/趾尖端的再生受一个基因调控网络的控制，该网络重现了肢体发育的某些方面，而未能激活这一发育程序会导致纤维性伤口愈合。
