Determinants of cellular plasticity in the regenerating kidney

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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.