Chen Shuang, Brunskill Eric W, Potter S Steven, Dexheimer Phillip J, Salomonis Nathan, Aronow Bruce J, Hong Christian I, Zhang Tongli, Kopan Raphael
Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA.
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45220, USA.
Dev Cell. 2015 Oct 12;35(1):49-62. doi: 10.1016/j.devcel.2015.09.009.
During fetal development, nephrons of the metanephric kidney form from a mesenchymal progenitor population that differentiates en masse before or shortly after birth. We explored intrinsic and extrinsic mechanisms controlling progenitor lifespan in a transplantation assay that allowed us to compare engraftment of old and young progenitors into the same young niche. The progenitors displayed an age-dependent decrease in proliferation and concomitant increase in niche exit rates. Single-cell transcriptome profiling revealed progressive age-dependent changes, with heterogeneity increasing in older populations. Age-dependent elevation in mTor and reduction in Fgf20 could contribute to increased exit rates. Importantly, 30% of old progenitors remained in the niche for up to 1 week post engraftment, a net gain of 50% to their lifespan, but only if surrounded by young neighbors. We provide evidence in support of a model in which intrinsic age-dependent changes affect inter-progenitor interactions that drive cessation of nephrogenesis.
在胎儿发育过程中，后肾的肾单位由间充质祖细胞群体形成，这些祖细胞在出生前或出生后不久集体分化。我们在一项移植试验中探索了控制祖细胞寿命的内在和外在机制，该试验使我们能够比较老年和年轻祖细胞在相同年轻微环境中的植入情况。祖细胞表现出增殖随年龄增长而下降，同时微环境退出率增加。单细胞转录组分析揭示了随年龄增长的渐进性变化，老年群体中的异质性增加。mTor随年龄增长而升高以及Fgf20降低可能导致退出率增加。重要的是，30%的老年祖细胞在植入后长达1周仍留在微环境中，其寿命净增加50%，但前提是被年轻邻居包围。我们提供的证据支持这样一种模型，即内在的年龄依赖性变化会影响祖细胞间的相互作用，从而驱动肾发生的停止。
