Determinants of cellular plasticity in the regenerating kidney

由于胚胎干细胞储备的丧失，大多数组织的增殖和再生能力在出生后迅速下降。然而，正常情况下静止的组织，如肾、胰腺和肝脏等，在损伤后可以不同程度地再生。在一个模型中，研究表明，静止的组织中含有一组循环缓慢且未分化的细胞，每当损伤发生时，这些细胞就会随时复制。或者，其他报告强调有丝分裂后和特化的上皮细胞类型去分化的能力，以此作为重建干细胞库以应对损伤的一种手段。尽管后者的机制尚不清楚，但我们之前的工作描述了肠上皮再生过程中的一种暂时性细胞类型，这种细胞类型来自于辐射和化学诱导的损伤导致的去分化祖细胞。最近，我们发现肠道中这些再生干细胞的显著标志之一，分泌因子聚集素(Clu)，在肾脏低氧应激后的再生肾单位中也上调。根据我们的初步谱系追踪数据，我们假设CLU标记了一个独特的干细胞群体，这是肾脏再生所必需的。我们的研究计划旨在对Clu+肾小管上皮细胞在动态平衡和再生条件下的转录图谱进行分析，并在谱系追踪和体外有机物分析中评估它们的再生能力。此外，我们将开发基于有机物的策略来研究Clu作为细胞自主驱动的肾小管修复的功能。最后，长期目标将是追求这些模型，以识别调控肾小管修复的新基因。细胞分化和谱系分化并不像人们曾经认为的那样是单向的过程，而是可以根据生物学背景采取多个过程。这项研究计划将解决长期存在的问题，即肾小管重编程和上皮可塑性是如何在肾脏中调节的，从而导致我们对成人干细胞的基础知识取得重要进展。这项研究计划还有可能为生物工程等应用领域未来的组织制造程序提供信息，这些领域依赖于利用干细胞的再生能力。

The proliferative and regenerative capacity of most tissues declines rapidly after birth due to loss of their embryonic stem cell reserves. Nevertheless, normally quiescent tissues such as the kidney, pancreas and liver, etc. can regenerate to varying degrees following injury. In one model, studies have suggested that quiescent tissues harbor a subset of slowly cycling and undifferentiated cells that are poised to replicate whenever damage occurs. Alternatively, other reports emphasize the ability of postmitotic and specialized epithelial cell types to de-differentiate as a means to re-establish a pool of stem cells in response to injury. Although the mechanisms underlying the latter remain unresolved, our previous work characterized a transitory cell type during gut epithelial regeneration that is derived from de-differentiating progenitors in response to irradiation and chemical-induced injury. More recently, we have found that one of the prominent markers of these regenerative stem cells in the gut, the secreted factor Clusterin (Clu), is also upregulated in regenerating nephrons following hypoxic stress in kidneys. Based on our preliminary lineage tracing data, we hypothesize that Clu marks a distinct stem cell population that is essential for regeneration of the kidney. Our research program aims to transcriptionally profile Clu+ tubular epithelial cells under homeostatic and regenerative conditions, as well as assess their regenerative capacity in lineage tracing and ex vivo organoid assays. Furthermore, we will develop organoid-based strategies to study the function of Clu as a cell autonomous driver of tubular repair. Finally, the long-term objective will be to pursue these models to identify novel genes regulating tubular repair. Cellular differentiation and lineage specification are not unidirectional processes as once believed, but rather can take on multiple courses depending on the biological context. This research program will address long-standing questions regarding how tubular reprogramming and epithelial plasticity are regulated in the kidney, thus leading to important advances in our fundamental knowledge of adult stem cells. This research program also has the potential to inform future tissue fabrication procedures in applied fields such as bioengineering, which rely on harnessing the regenerative capacity of stem cells.