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因其胚胎干细胞储备的丧失而出生后出生后迅速下降。然而，肾脏，胰腺和肝脏等通常静止的组织会在受伤后再生到不同程度。在一个模型中，研究表明，静态组织具有缓慢循环和未分化细胞的子集，每当发生损害时，它们都可以复制。另外，其他报告强调了有丝分裂后和专业上皮细胞类型的能力去分化，以此作为响应损伤响应损伤的干细胞池的一种手段。尽管后者的基础机制仍未解决，但我们以前的工作表征了肠道上皮再生过程中的暂时细胞类型，该细胞类型是从降低祖细胞源自辐射和化学诱导损伤的响应中得出的。最近，我们发现肠道中这些再生干细胞的突出标记之一是分泌的因子簇（CLU），在肾脏低氧应激后再生肾后果也被上调。基于我们的初步谱系跟踪数据，我们假设CLU标志着一种独特的干细胞种群，这对于肾脏的再生至关重要。我们的研究计划旨在在稳态和再生条件下进行转录介绍CLU+管状上皮细胞，并评估其在谱系跟踪和离体器官测定中的再生能力。此外，我们将开发基于器官的策略，以研究CLU作为管状修复的细胞自主驱动器的功能。最后，长期目标将是追求这些模型以鉴定调节管状修复的新型基因。细胞分化和谱系规范不是曾经认为的单向过程，而是可以根据生物学背景进行多个课程。该研究计划将解决有关肾脏中如何调节管状重编程和上皮可塑性的长期问题，从而导致我们对成年干细胞的基本知识的重要进展。该研究计划还具有为未来的组织制造程序（例如生物工程）提供信息的潜力，这些程序依赖于利用干细胞的再生能力。