Unraveling the mechanisms of Senescence-Associated Stemness in 3D Kidney Structures

Abstract

During aging, senescent cells accumulate in the kidney, impairing function and intrinsic repair. These senescent cells develop a distinct, heterogeneous Senescence-Associated Secretory Phenotype (SASP), releasing among pro-inflammatory cytokines and proteases. While transient SASP secretion is thought to be beneficial for regeneration after injury, chronic presence of SASP molecules may be harmful to cells in the surrounding tissue. Moreover, the accumulation of senescent cells in the kidney has been linked to the progression of Chronic Kidney Disease. In organs like the liver, SASP molecules have been found to promote stemness and impair cell differentiation. In this manner, SASP molecules could potentially prevent regeneration from fully taking place. Nevertheless, it remains unclear through which mechanisms the SASP impairs regeneration in the kidney, and whether this occurs through a similar mechanism of promoting stemness and hindering differentiation. This study shows that the SASP, secreted by cisplatin-induced senescent renal proximal tubular epithelial cells (RPTECs), hinders the full differentiation of iPSC-derived 3D renal structures, keeping cells in a progenitor-like state. These effects seem to be dependent on the activation of the NF-κB pathway in the cells recipient of the SASP. Specifically, renal progenitor cells exposed to the SASP maintain high expression of CD44 and express less of NPHS1, a marker for podocytes. At the same time, the differentiation of cells expressing UMOD, a marker of the Loop of Henle, is not affected. Ultimately, emerging senescence-targeting approaches could mitigate the detrimental effects of the SASP in regeneration, and hold promise in preventing the onset of CKD in elderly patients post-cisplatin cancer treatment.