Emerging roles of transit‐amplifying cells in tissue regeneration and cancer

Abstract

Most regenerative tissues employ transit-amplifying cells (TACs) that are positioned in between stem cells and differentiated progeny. In a classical hierarchical model, stem cells undergo limited divisions to produce TACs, which then proliferate rapidly to expand the system and produce diverse differentiated cell types. Although TACs are indispensable for generating tissues, they have been largely viewed as a transit point between stem cells and downstream lineages. Studies in the past few years however, have revealed some fascinating biology and unanticipated functions of TACs. In the hair follicle, recent findings have placed TACs as key players in tissue regeneration by coordinating tissue production, governing stem cell behaviors, and instructing niche remodeling. In the hematopoietic system, rather than being transient, some TACs may participate in long-term hematopoiesis under steady state. Here, we compare and summarize recent discoveries about TACs in the hair follicle and the hematopoietic system. We also discuss how TACs of these two tissues contribute to the formation of cancer.

Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma

“…We identified cells that express both genes associated with neuronal differentiation and stemness as being associated with drug-tolerance. Similar populations of cells have been identified in other normal developmental hierarchies 36–37 , and in cancer, and have been termed transit amplifying cells 38,39 or in the neural context, “activated quiescent neural progenitor cells”. These cells have been shown to harbor a phenotype that is more differentiated than stem cells, and to harbor increased proliferative potential compared to quiescent stem cells or terminally differentiated neurons.…”

Acute systemic loss of Mad2 leads to intestinal atrophy in adult mice

“…We did observe a weak phenotype in the hematopoietic system, mostly in spleen. A possible explanation for this is the proliferation rate within these tissues, as both intestinal crypt cells and hematopoietic stem cells produce rapidly proliferating cells 31 , 33 , 34 . Notably, while loss of p53, or p53 mutation enhances CIN tolerance in MEFs 6 , we did not observe striking differences between the phenotypes of Mad2 f/f− ; Cre-ERT2 and Mad2 f/f ; p53 3f/f ; Cre-ERT2 adult mice, suggesting that in jejunum/ileum p53 loss is not sufficient to rescue apoptotic cell death in a high-grade CIN background .…”

Transit amplifying cells coordinate mouse incisor mesenchymal stem cell activation

“…TACs are committed and proliferative direct lineage of primed SCs 8 . For most of the mammalian organs, upon the completion of development or regeneration, the TACs vanish and tissue growth stops 9 . TACs induction, maintenance, and differentiation therefore must be rigorously controlled and directed by molecular signaling and cellular microenvironment.…”