Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA; Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
Cell Stem Cell. 2018 Jan 4;22(1):119-127.e3. doi: 10.1016/j.stem.2017.11.009. Epub 2017 Dec 14.
The clonal complexity of adult stem cell pools is progressively lost during homeostatic turnover in several tissues, suggesting a decrease in the number of stem cells with distinct clonal origins. The functional impact of reduced complexity on stem cell pools, and how different tissue microenvironments may contribute to such a reduction, are poorly understood. Here, we performed clonal multicolor lineage tracing of skeletal muscle stem cells (MuSCs) to address these questions. We found that MuSC clonal complexity is maintained during aging despite heterogenous reductions in proliferative capacity, allowing aged muscle to mount a clonally diverse, albeit diminished, response to injury. In contrast, repeated bouts of tissue repair cause a progressive reduction in MuSC clonal complexity indicative of neutral drift. Consistently, biostatistical modeling suggests that MuSCs undergo symmetric expansions with stochastic fate acquisition during tissue repair. These findings establish distinct principles that underlie stem cell dynamics during homeostatic aging and muscle regeneration.
成体干细胞在多种组织的稳态更新过程中，其克隆复杂性逐渐丧失，这表明具有不同克隆起源的干细胞数量减少。复杂性降低对干细胞库的功能影响，以及不同组织微环境如何促成这种降低，目前还知之甚少。在这里，我们对骨骼肌干细胞（MuSCs）进行了克隆多色谱系追踪，以解决这些问题。我们发现，尽管增殖能力存在异质性降低，但 MuSC 克隆复杂性在衰老过程中得以维持，从而使衰老的肌肉能够对损伤产生克隆多样化但减少的反应。相比之下，反复的组织修复会导致 MuSC 克隆复杂性逐渐降低，表明出现了中性漂变。一致地，生物统计学模型表明，MuSCs 在组织修复过程中经历了随机命运获取的对称扩展。这些发现确立了在稳态衰老和肌肉再生过程中干细胞动力学的不同原则。
