The Act of Controlling Adult Stem Cell Dynamics: Insights from Animal Models

Abstract

Adult stem cells (ASCs) are the undifferentiated cells that possess self-renewal and differentiation abilities. They are present in all major organ systems of the body and are uniquely reserved there during development for tissue maintenance during homeostasis, injury, and infection. They do so by promptly modulating the dynamics of proliferation, differentiation, survival, and migration. Any imbalance in these processes may result in regeneration failure or developing cancer. Hence, the dynamics of these various behaviors of ASCs need to always be precisely controlled. Several genetic and epigenetic factors have been demonstrated to be involved in tightly regulating the proliferation, differentiation, and self-renewal of ASCs. Understanding these mechanisms is of great importance, given the role of stem cells in regenerative medicine. Investigations on various animal models have played a significant part in enriching our knowledge and giving In Vivo in-sight into such ASCs regulatory mechanisms. In this review, we have discussed the recent In Vivo studies demonstrating the role of various genetic factors in regulating dynamics of different ASCs viz. intestinal stem cells (ISCs), neural stem cells (NSCs), hematopoietic stem cells (HSCs), and epidermal stem cells (Ep-SCs).

Keywords: adult stem cell; animal model; epidermal stem cell; hematopoietic stem cell; intestinal stem cell; neural stem cell; signaling pathway.

Figure 1

Genetic regulation of ISC (intestinal stem cell) dynamics. ISCs maintain all the differentiated cell types in the intestinal epithelium. The figure shows a magnified crypt morphology with a distribution of different cell types along the crypt and various signaling pathways modulating ISC dynamics. The direction of arrows near the pathways indicates upregulation or downregulation. In general, Wnt, Notch, JAK/STAT, and MAPK pathways are promoters of proliferation in ISCs, whereas TGF-β and Hippo are negative regulators. Loss of Wnt and hedgehog leads to differentiation defects with loss of crypt proliferation and loss of ISCs, although there is contradicting evidence where hedgehog increases proliferation. The notch is also necessary to maintain ISCs in their progenitor phenotype as loss of Notch was found to induce differentiation. JAK/STAT also plays a role in cell fate specification as loss of signaling causes defective differentiation and failure in specification.

Figure 2

Genetic regulation of NSC (neural stem cell) dynamics. The role of different pathways in maintaining NSC proliferation, differentiation, and self-renewal are shown. In NSCs, Wnt, MAPK, and Hedgehog signaling acts as a positive regulator of proliferation where its upregulation increases NSC number. TGF-β, Notch, and Hippo pathways act to maintain the quiescent state of NSCs and promote stemness. JAK/STAT pathway is involved in decisions of lineage specification where upregulated signal induces astrocyte differentiation and downregulated signal induces neural differentiation. MAPK is also involved in NSC migration towards the site of injury.

Figure 3

Genetic regulation of HSC (hematopoietic stem cell) dynamics. Hematopoietic stem cells give rise to all the differentiated cell types in the blood. Key signaling pathways regulating the proliferation, differentiation, and self-renewal of HSCs are shown. Upregulation of Wnt signaling generally increases HSC and progenitor proliferation as well as increasing HSC survival and number during embryonic development. Notch signaling maintains the multipotency of the lymphoid and myeloid progenitors. Hedgehog and TGF-β increase LSK HSCs. Increased JAK/STAT, on the other hand, decreases the number of LSK HSCs, decreases repopulation capacity, and increases proliferation. Downregulation of the MAPK pathway causes HSC attrition, with bone marrow aplasia, anemia, leukopenia, and inhibited differentiation. Inhibition of MAPK signaling is reported to promote self-renewal as well.

Figure 4

Genetic regulation of EpSc (epidermal stem cell) dynamics. Proliferation, differentiation, and self-renewal in the mammalian epidermis occur mainly due to interfollicular epithelial stem cells and hair bulge stem cells. Signaling pathways regulating these stem cells are indicated. (A) represents the effect of the Wnt signaling pathway on EpSc. Active β-catenin expands the stem cell compartment and induces differentiation towards hair follicle lineage. In contrast, loss of β-catenin leads to a complete lack of hair follicles with the formation of dermal cysts and differentiation towards epidermal lineage. (B) represents the role of TGF-β signaling. Overactivation of BMP leads to premature differentiation with the formation of cysts having cells of hair follicle lineage, whereas lack of BMP leads to a dramatic increase in stem cells, forming dermal cysts lined with stem cells and hyperplasia of the interfollicular epidermis. (C) shows the role of MEK/ERK and Notch signaling. Activation of MEK or Ras leads to hyperproliferation in the epidermis, leading to epidermal thickening. MEK and Notch pathways promote proliferation and inhibit differentiation. Loss of Notch leads to cyst formation and complete lack of hair, along with hair follicle degeneration. Inhibition of Notch leads to premature entry into catagen. (D) shows the role of the Hippo pathway. Loss of Hippo or activation of YAP expands the stem cell compartment, decreases differentiation, and leads to multilayered epithelium with abundant progenitor cells. Activation of the Hippo leads to a thinner epidermis formation, with impaired epithelial barrier function and loss of stem cells. (E) Shh activation induces anagen phase, whereas loss of Shh leads to reduced hair follicles (C). JAK/STAT inhibition also shows accelerated entry into the anagen phase along with increased proliferation in the hair germ area.