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

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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. WIREs Dev Biol 2017, 6:e282. doi: 10.1002/wdev.282

The hair cycle and hair follicle structures. The hair follicle cycles between a regenerative phase (anagen), a destruction phase (catagen), and a resting phase (telogen). Telogen hair follicles contain stem cells located in the outer bulge layer and the hair germ. Proliferation of the hair germ generates the matrix in anagen, which are transit‐amplifying cells of the hair follicles (HF‐TACs). Proliferation of the bulge generates the outer root sheath (ORS) that wraps around the anagen hair follicles. Differentiated cells, including the hair shaft, the inner root sheath (IRS), and the companion layer, are produced by the HF‐TACs. During catagen, HF‐TACs are destroyed. The remaining ORS cells form a new bulge responsible for the next round of the hair cycle.
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Comparison between the hair follicle system and the hematopoietic system. The diagram summarizes the lineage hierarchy in the hair follicle system and the hematopoietic system. In the hair follicle, bulge stem cells (Bu‐SCs) are more quiescent than the hair germ. Transit‐amplifying cells (TACs) are produced by the hair germ. Through Sonic Hedgehog (SHH), TACs send feedback signals to the Bu‐SCs and at the same time promote critical changes of the surrounding tissues including the dermal papilla and adipocytes. Hematopoietic stem cells (HSCs) generate multipotent progenitors (MPPs) upon transplantation. MPPs further produce common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs) to generate downstream effector cells of the lymphoid or myeloid lineages, albeit in the short term. During homeostasis, HSCs are mostly quiescent and MPPs display long‐term multilineage contributions. TACs of the hair follicles cannot be transformed by oncogenic mutations. However, MPPs and their committed progenitors downstream can be transformed readily to initiate leukemia.
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Fluorescence‐activated cell sorting (FACS) strategies for purification of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) and functional differences among different subtypes of MPPs. Cell surface markers used to purify HSCs and MPPs. Different strategies have been employed to enrich HSCs and MPPs. Two common strategies are listed here: In strategy I, lineage‐negative (Lin−) cells are bone marrow cells that do not express mature hematopoietic cell lineage markers. MPPs are purified as cells within the LSK (Lin−, Sca1+, cKit+) cells that do not display long‐term lineage reconstitution ability upon transplantation. In strategy II, distinct MPP subsets are further separated by additional surface markers. MPP1–MPP4 display different lineage biases upon transplantations.
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Hair follicle's transit‐amplifying cells (HF‐TACs) regulate both the hair follicle stem cells (HF‐SCs) and the niche. HF‐TACs secrete Sonic Hedgehog (SHH) to activate the HF‐SCs located in the bulge (Bu‐SC). SHH also enhances the expression of Noggin and Fgf7 in the dermal papilla. All three factors together promote HF‐TACs’ own proliferation. SHH from HF‐TACs also promotes adipocyte formation from adipocyte precursors in the dermal niche.
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Marker gene expression in distinct layers of the anagen and telogen hair follicles. Markers that are commonly used to distinguish CD34+ bulge, K6+ bulge, transit‐amplifying cells (TACs), outer root sheath (ORS), companion layer, inner root sheath (IRS, including Henle's layer, Huxley's layer, and the IRS cuticle), hair shaft (including hair cuticle, cortex, and medulla), and dermal papilla (DP) are shown. AP, alkaline phosphatase; Pcad, P‐Cadherin; Nog, Noggin.
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