Coexistence of quiescent and active adult stem cells in mammals

Abstract

Adult stem cells are crucial for physiological tissue renewal and regeneration after injury. Prevailing models assume the existence of a single quiescent population of stem cells residing in a specialized niche of a given tissue. Emerging evidence indicates that both quiescent (out of cell cycle and in a lower metabolic state) and active (in cell cycle and not able to retain DNA labels) stem cell subpopulations may coexist in several tissues, in separate yet adjoining locations. Here, we summarize these findings and propose that quiescent and active stem cell populations have separate but cooperative functional roles.

Fig. 1

Stem cell locations in hair follicle, gut, and bone marrow. (A) Hair follicle structure with quiescent (bulge) and active (hair germ) stem/progenitor cells. Bulge area typically maintains quiescent stem cells, whereas DP provides stimulatory signals. Only during development and under injury condition, bulge stem cells give rise to stem cells in epidermis. (B) Intestinal crypt structure with quiescent (+4) and active CBC (Lgr5⁺) stem cells, as well as TA and mesenchymal cells. (C) Quiescent HSCs located in the endosteal region where osteoblastic lining, endothelial, CAR, and other cells form the endosteal region and active HSCs located in the central marrow region, which lacks osteoblastic cells.

Fig. 2

DP position determines state of stem/progenitor cells in hair follicle. (A) Hair cycle. At the start of anagen, DP is proximal to hair germ and bulge. Stem/progenitor cells in hair germ (a structure below the bulge) are activated by DP first, whereas stem cells remain quiescent in bulge. When hair germ cells enter the hair matrix, then stem cells in bulge are activated to replenish lost hair germ cells. During anagen, active hair germ stem cells give rise to TA cells, which in turn support hair growth. DP is pushed down from bulge because of fast expansion of progenitor cells. In catagen, DP retracts toward bulge. (B) Co-staining of BrdU with phosphorylated-Akt shows relationship between quiescent stem cells (yellow arrow) and active stem cells (red arrows) in bulge and hair germ. [Reprinted by permission from John Wiley and Sons, Incorporated, AlphaMed Press, p. 2834 of (20).] (C and D ) CD34⁺Lgr5⁻ and CD34⁺Lgr5⁺ stem cells, respectively, located inside and next to bulge area (C), which is consistent with Lgr5⁺ stem cells located adjacent to LRCs (D). [Reprinted by permission from Macmillan Publishers, Limited, pp. 1292 and 1293 of (19).]

Fig. 3

Two models for stem cell-based tissue self-renewal and regeneration. (A) Prevailing model of a single stem cell population located in the niche. Asymmetric division is the key mechanism to maintain balance between self-renewal and differentiation. (B) Proposed alternative and complementary model: co-existing quiescent and active stem cell populations located in adjacent zones with corresponding inhibitory and stimulatory signals. Quiescent stem cells replace damaged active stem cells (heavy arrow). Conversely, active stem cells may replace lost quiescent stem cells (light arrow). A negative feedback from either active stem cells (dashed line) or their progeny (solid line) may contribute to prevention of quiescent stem cells from activation.

Fig. 4

Zoned stem cell population and the associated microenvironmental signals. (A) Bulge area typically provides Wnt-off and BMP-on signals thus maintaining quiescent stem cells, whereas DP provides stimulatory (Wnt-on and BMP-off) signals. (B) Similarly, in intestinal crypt (+4) ISCs are maintained by Wnt-off and BMP-on signals. In contrast, CBC (Lgr5⁺) stem cells are exposed to Wnt-on but BMP-off signals. (C) Quiescent HSCs located in the endosteal zone where osteoblastic lining cells provide dominant inhibitory signals including BMP, OPN, and sFRP1. In contrast, HSCs located in the central marrow zone are stimulated by endothelial, megakaryocyte, and CAR cells secreting Wnt, FGF, and SDF1.