Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration

Aging induces a progressive decline in tissue function, which has been attributed to a decrease in stem cell function. A major factor driving this decline is the aging of the stem cell niche but elucidating molecular mechanisms of the niche aging and its effects on stem cell regulation remain a challenge. Here, we use the Caenorhabditis elegans distal tip cell (DTC), the mesenchymal niche that employs Notch signaling to regulate germline stem cells (GSCs), as an in vivo niche aging model and delineate the molecular details of the DTC/niche aging process and its consequences on GSC function and tissue integrity. Using Notch-dependent transcriptional activation as a direct readout of GSC-DTC/niche interaction and its transcriptional activity as a readout for GSC function, we find that an age-dependent reduction in Notch transcription occurs both at the tissue and the cellular levels, but with its activity at the chromosomal loci remains unaffected. This overall reduction is due to an age-dependent progressive shift in the spatial pattern of Notch-dependent transcription in the germline, resulting in a shift of the GSC pool location and disruption of the tissue integrity. We show that the position of the DTC/niche nucleus determines the location of the Notch-responsive GSC pool, with its correlation to the structure and morphology of the DTC/niche, which also changes during aging. Our findings demonstrate that the stem cell niche undergoes structural and morphological changes during aging and reveal a critical link between these changes and the spatiotemporal regulation of stem cell function.