Determinants of cellular plasticity in the regenerating kidney

再生肾脏细胞可塑性的决定因素

• 批准号: RGPIN-2022-03384
• 负责人: Gregorieff, Alex
• 金额: $ 3.28万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761952
• 关键词: Determinants; cellular; plasticity; regenerating; kidney

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.

大多数组织的增殖和再生能力在出生后由于胚胎干细胞储备的损失而迅速下降。然而，通常静止的组织如肾、胰腺和肝等在损伤后可以不同程度地再生。在一个模型中，研究表明，静止的组织含有一个缓慢循环和未分化的细胞亚群，这些细胞在损伤发生时随时准备复制。或者，其他报道强调有丝分裂后和特化上皮细胞类型去分化的能力作为响应损伤重建干细胞库的手段。虽然后者的机制尚未解决，我们以前的工作特点是肠上皮再生过程中的一种过渡性细胞类型，该细胞来源于对辐射和化学诱导的损伤作出反应的去分化祖细胞。最近，我们已经发现，这些再生干细胞在肠道中的突出标志物之一，分泌的促凝素因子（Clu），也在肾脏缺氧应激后的再生肾单位中上调。基于我们初步的谱系追踪数据，我们假设Clu标志着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转录配置文件Clu+肾小管上皮细胞在稳态和再生条件下，以及评估其再生能力的谱系追踪和离体类器官测定。此外，我们将开发基于类器官的策略来研究Clu作为肾小管修复的细胞自主驱动程序的功能。最后，长期目标将是追求这些模型，以确定新的基因调控肾小管修复。细胞分化和谱系特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，即如何在肾脏中调节肾小管重编程和上皮可塑性，从而使我们对成体干细胞的基础知识取得重要进展。这项研究计划也有可能为生物工程等应用领域的未来组织制造程序提供信息，这些应用领域依赖于利用干细胞的再生能力。