Telocytes Twenty Years on: A Critical Reappraisal of Identity, Function, and Pathological Relevance

Telocytes are stromal cells defined by extremely long, moniliform prolongations termed telopodes and have been described in most mammalian organs since their formal designation in 2010. During the past two decades, the field has expanded from ultrastructural organ-mapping to hypotheses concerning stem-cell niche regulation, extracellular-vesicle-mediated communication, fibrosis, inflammation, and cancer-associated stromal remodelling. This expansion, however, has also generated methodological heterogeneity, with frequent reliance on non-specific markers such as CD34, PDGFRα, vimentin, and c-kit, often without ultrastructural validation or functional perturbation. In this critical review, we reassess the evidential status of major claims in telocyte biology, distinguishing robustly demonstrated mechanisms from plausible but incompletely proven hypotheses. The strongest functional evidence remains the conditional ablation of Wnt secretion in intestinal Foxl1-/Gli1-expressing subepithelial telocytes, which demonstrates their necessity for stem-cell niche maintenance. By contrast, most evidence from cardiac, dermal, reproductive, and fibrotic tissues remains supplementation-based or correlative. We propose a unified Stromal Network Organiser framework, in which telocytes are interpreted as tissue-specific stromal network cells whose dysfunction may involve not only numerical loss, but also telopode fragmentation, contact uncoupling, paracrine alteration, stromal replacement, and failed niche signalling. To improve methodological clarity, we introduce a two-dimensional evaluation matrix that separates identification confidence from functional confidence. We argue that the next decade of telocyte research should prioritise loss-of-function experiments outside the intestine, independent replication of foundational single-laboratory concepts, and high-resolution multi-organ correlative ultrastructural atlases.