Dying cells as architects of the stem cell niche: a conserved mechanism driving tissue regeneration and tumor therapy resistance

The stem cell niche plays a pivotal non–cell-autonomous role in maintaining stem cell function, yet it can be disrupted by tissue injury or cancer therapy. Here, we propose that dying cells induced by external insults actively construct a novel, enhanced stem cell niche that facilitates stem cell survival under harsh conditions. This phenomenon is evolutionarily conserved across diverse species and evolutionary hierarchies, contributing critically to both tissue regeneration and tumor recurrence. In the context of tissue regeneration, dying differentiated daughter cells reinforce stemness by secreting ligands and protective factors that support self-renewal. Additionally, damaged environmental cells, including stromal and inflammatory cells, contribute to niche reconstruction through paracrine signaling. The clearance of dying cells further modulates the niche to better support stem cell for regeneration or tumor regrowth. Among cell death modalities, apoptosis, particularly caspase-3–mediated apoptosis, plays a central role by orchestrating microenvironmental remodeling and activating pro-stemness signaling pathways. These mechanisms are also hijacked by cancer cells to reinforce therapy resistance, which are often overlooked. Unraveling how dying cells dynamically reshape the stem cell niche provides novel insights into regenerative biology and may inform therapeutic strategies to overcome tumor therapy resistance.