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Review
. 2023 May;24(5):334-354.
doi: 10.1038/s41580-022-00568-6. Epub 2023 Mar 15.

Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity

Antoine de Morree  1   2   3 , Thomas A Rando  4   5   6   7
Affiliations
Review

Regulation of adult stem cell quiescence and its functions in the maintenance of tissue integrity

Antoine de Morree et al. Nat Rev Mol Cell Biol. 2023 May.

Abstract

Adult stem cells are important for mammalian tissues, where they act as a cell reserve that supports normal tissue turnover and can mount a regenerative response following acute injuries. Quiescent stem cells are well established in certain tissues, such as skeletal muscle, brain, and bone marrow. The quiescent state is actively controlled and is essential for long-term maintenance of stem cell pools. In this Review, we discuss the importance of maintaining a functional pool of quiescent adult stem cells, including haematopoietic stem cells, skeletal muscle stem cells, neural stem cells, hair follicle stem cells, and mesenchymal stem cells such as fibro-adipogenic progenitors, to ensure tissue maintenance and repair. We discuss the molecular mechanisms that regulate the entry into, maintenance of, and exit from the quiescent state in mice. Recent studies revealed that quiescent stem cells have a discordance between RNA and protein levels, indicating the importance of post-transcriptional mechanisms, such as alternative polyadenylation, alternative splicing, and translation repression, in the control of stem cell quiescence. Understanding how these mechanisms guide stem cell function during homeostasis and regeneration has important implications for regenerative medicine.

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Conflict of interest statement

Competing interests statement

The authors declare no competing financial interests.

Figures

Figure 1:
Figure 1:. Types of quiescent stem cells and their features.
A) Populations of quiescent stem cells have been identified in several tissues. The bone marrow harbors populations of quiescent hematopoietic stem cells (HSCs) , which are established in mice up to six weeks postnatally. HSCs are required to generate the progenitors that sustain the daily production of billions of blood cells and can regenerate the complete blood-cell system following transplantation or injury. Around 6% of mouse HSCs enter the cell cycle each day, though distinct subsets display different activation parameters,,. Skeletal muscle contains a population of quiescent stem cells known as skeletal-muscle stem cells (MuSCs). MuSCs are established around two months after birth in mice. MuSCs are essential to generate the progenitors that regenerate skeletal muscles–. Around 0.3–1.0% of mouse MuSCs enter the cell cycle each day, depending on the muscle, and their progeny fuse with mature myofibers, though their impact on muscle homeostasis is limited,,. A quiescent population of mesenchymal stem cells also called fibro-adipogenic progenitors (FAPs) supports muscle regeneration and homeostasis,. Around 1% of mouse FAPs enters the cell cycle daily. The adult brain hosts populations of quiescent neural stem cells (NSCs) in the subventricular zone lining the lateral ventricles and in the subgranular zone of the dentate gyrus in the hippocampus. NSCs are established in mice by the second week after birth. They are required to generate the progenitors that sustain continued formation of new neurons, astrocytes and oligodendrocytes. Around 12% of mouse NSCs enter the cell cycle each day. The hair follicles in the skin harbor populations of quiescent hair follicle stem cells (HFSCs). Hair follicles undergo cyclic rounds of growth (anagen), degeneration (catagen) and rest (telogen), termed the “hair cycle”. Quiescent HFSCs are established by 3 weeks after birth at the end of the first hair cycle in mice. During anagen, HFSCs are essential to generate the progenitors that sustain hair growth. They generate the progeny that will start a new hair cycle. Around 0.5% of mouse HFSCs in the bulge [G] enter the cell cycle each day during telogen. Overview of the tissue, time of establishment and spontaneous activation rates of five common adult quiescent stem cell types: HSCs,,–, MuSCs,–, FAPs–, NSCs,,, and HFSCs,,. B) Quiescent stem cells display a number of distinct features compared to their activated counterparts and undergo different processes, including maintenance of the quiescent state, exit from the quiescent state (activation), and re-entry into the quiescent state (re-quiescence, or self-renewal). At any point in time, quiescent stem cells must ensure survival and may undergo apoptosis. Quiescent stem cells possess several features distinct from their activated counterparts, including small cell size, low RNA and protein content, low mTOR signaling and mitochondrial activity, high use of glycolysis and more heterochromatin, as well as stem cell type specific expression of transcription factors PAX7 (Paired Box 7, MuSCs), TCF3 and TCF4 (Transcription Factor 3 and 4, HFSCs), HOXB5 and TCF15 (Homeobox B5 and Transcription Factor 15, HSCs), and ID3 (Inhibitor of DNA Binding 3, NSCs).
Figure 1:
Figure 1:. Types of quiescent stem cells and their features.
A) Populations of quiescent stem cells have been identified in several tissues. The bone marrow harbors populations of quiescent hematopoietic stem cells (HSCs) , which are established in mice up to six weeks postnatally. HSCs are required to generate the progenitors that sustain the daily production of billions of blood cells and can regenerate the complete blood-cell system following transplantation or injury. Around 6% of mouse HSCs enter the cell cycle each day, though distinct subsets display different activation parameters,,. Skeletal muscle contains a population of quiescent stem cells known as skeletal-muscle stem cells (MuSCs). MuSCs are established around two months after birth in mice. MuSCs are essential to generate the progenitors that regenerate skeletal muscles–. Around 0.3–1.0% of mouse MuSCs enter the cell cycle each day, depending on the muscle, and their progeny fuse with mature myofibers, though their impact on muscle homeostasis is limited,,. A quiescent population of mesenchymal stem cells also called fibro-adipogenic progenitors (FAPs) supports muscle regeneration and homeostasis,. Around 1% of mouse FAPs enters the cell cycle daily. The adult brain hosts populations of quiescent neural stem cells (NSCs) in the subventricular zone lining the lateral ventricles and in the subgranular zone of the dentate gyrus in the hippocampus. NSCs are established in mice by the second week after birth. They are required to generate the progenitors that sustain continued formation of new neurons, astrocytes and oligodendrocytes. Around 12% of mouse NSCs enter the cell cycle each day. The hair follicles in the skin harbor populations of quiescent hair follicle stem cells (HFSCs). Hair follicles undergo cyclic rounds of growth (anagen), degeneration (catagen) and rest (telogen), termed the “hair cycle”. Quiescent HFSCs are established by 3 weeks after birth at the end of the first hair cycle in mice. During anagen, HFSCs are essential to generate the progenitors that sustain hair growth. They generate the progeny that will start a new hair cycle. Around 0.5% of mouse HFSCs in the bulge [G] enter the cell cycle each day during telogen. Overview of the tissue, time of establishment and spontaneous activation rates of five common adult quiescent stem cell types: HSCs,,–, MuSCs,–, FAPs–, NSCs,,, and HFSCs,,. B) Quiescent stem cells display a number of distinct features compared to their activated counterparts and undergo different processes, including maintenance of the quiescent state, exit from the quiescent state (activation), and re-entry into the quiescent state (re-quiescence, or self-renewal). At any point in time, quiescent stem cells must ensure survival and may undergo apoptosis. Quiescent stem cells possess several features distinct from their activated counterparts, including small cell size, low RNA and protein content, low mTOR signaling and mitochondrial activity, high use of glycolysis and more heterochromatin, as well as stem cell type specific expression of transcription factors PAX7 (Paired Box 7, MuSCs), TCF3 and TCF4 (Transcription Factor 3 and 4, HFSCs), HOXB5 and TCF15 (Homeobox B5 and Transcription Factor 15, HSCs), and ID3 (Inhibitor of DNA Binding 3, NSCs).
Figure 2:
Figure 2:. Key pathways active in quiescent stem cell processes.
Schematic highlighting key signaling pathways that are active during quiescence maintenance, exit, or entry. A) Signals from the niche to the quiescent stem cell that maintain the quiescencent state, such as ligands for Notch receptors including DLL1 (delta-like protein 1), and quiescence factors including BMP (bone morphogenic protein), TPO (thrombopoietin), calcitonin, and COLV (collagen V) to their respective receptors NOTCH, BMPRII (bone morphogenic protein receptor 2), TPOR (thrombopoietin receptor), and CALCR (calcitonin receptor). Such receptor-mediated signaling induces gene expression patterns that maintain the quiescent state, via signalling intermediates such as NICD-RBPj, and SMAD2–4. The expression of cell-cycle inhibitors such as p21 similarly invokes quiescence maintenance via inhibition of CDK4 or CDK6, which ensures that APC/C (anaphase promoting complex/cyclosome) and Rb (retinoblastoma) block E2F and S-phase entry. B) In response to growth factors, combined with the loss of signals listed in panel (A), phosphorylation cascades such as the PI3K-AKT pathway and the p38 MAP kinase pathway induce quiescence exit and cell cycle entry. C) To exit the cell cycle and enter the quiescent state, stem cells interact with NOTCH ligands and suppress the phosphorylation cascades listed in panel (B). In activated NSCs, TNFR1 (tumor necrosis factor 1 receptor) signaling through p38 MAP kinase is key for re-entry into the quiescent state. PTEN (phosphatase and tensin homolog), MEK1 (MAPK/ERK kinase 1), and ITPKB (inositoltrisphosphate 3-kinase b) inhibit AKT, while Sprouty1 (SPRY1) suppresses ERK signaling to stop mitogenic signaling. NICD, notch intracellular domain; RBPj, recombination signal binding protein for immunoglobulin kappa j region; CDK4/6, cyclin dependent kinase 4/6; PI3K, phosphatidylinositol-3 kinase.
Figure 3:
Figure 3:. Quiescence and the cell cycle.
A) Progression of somatic (stem) cells through the G1, S, G2 and M phases of the cell cycle involves intricate regulation by cyclins, cyclin-dependent kinases (CDKs), and their inhibitors. Central to cell-cycle entry and exit is the phosphorylation status of the retinoblastoma (Rb) proteins. Unphosphorylated Rb is chromatin-bound and blocks E2F transcription factors from inducing key proliferation genes. In pro-growth conditions, cyclin D activates CDK4 and CDK6, which phosphorylate (P) Rb and enable transcription of E2F target genes. Somatic stem cells enter the quiescent state early in G1, as a result of the downregulation of G1 cyclins — cyclin D and cyclin E (not shown) — and the upregulation of the CDK interacting protein (CIP) and kinase inhibitory protein (KIP) family of inhibitors, including p21, p27 and p57, which inhibit CDK4 and CDK6 (not shown). Quiescent stem cells can enter an ‘Alert’ state characterized by mTOR signalling and a shorter time to cell-cycle entry. B) The first division of the activation of quiescent stem cell is considerably longer than subsequent cell divisions. It is currently unclear whether that first division consists of a long G0 phase (top), a long G1 phase (middle), or several G0 sub-phases following each other in manner similar to the conventional cell cycle phases (bottom).
Figure 4:
Figure 4:. Post-transcriptional regulatory mechanisms in the nucleus that control stem cell quiescence.
Quiescent stem cells regulate mRNA and protein levels through a variety of post-transcriptional mechanisms. Selection of a cleavage and polyadenylation site (PAS) at the pre-mRNA can be blocked by cleavage and polyadenylation (CPA) factors. For example, polyadenylate-binding nuclear protein 1 (PABPN1) and U1 small nuclear RNA (U1 snRNA) block the use of a proximal PAS and thus favour the selection of a distal PAS and production of a mRNA isoform with a longer 3’ untranslated region (3’UTR); by contrast, NUDT21 (Nudix Hydrolase 21, also known as Cleavage and Polyadenylation Specificity Factor 25 KDa Subunit) favours the selection of a proximal PAS and production of a mRNA isoform with a shorter 3’UTR. The sequence of the pre-mRNA can be modified by ADAR (adenosine deaminase RNA specific) proteins, which deaminate adenosine nucleotides into inosine (A-I editing); by METLL methyltransferases that produce N6-methyladenosine (m6A), and by the SUN2 methyltransferase, which produces 5-methylcytosine (m5C). In addition, the mRNA sequence can be modified by alternative splicing; for example, the protein DEK (DEK Proto-Oncogene) can temporarily delay intron removal. The mature capped, spliced and polyadenylated mRNA is subsequently transported to the cytoplasm. METTL3,14, N6-adenosine-methyltransferase complex catalytic subunit 3,14; m6A, N6-Methyladenosine; m5C, 5-Methylcytosine; c-MPL, myeloproliferative leukemia protein, also known as thrombopoietin receptor; SUN2, sad1 and UNC84 domain containing 2; PAX3, paired-box 3; PDGFRa, platelet-derived growth factor receptor alpha; GLS, glutamine synthase; MDM2, mouse double minute 2 proto-oncogene; ADAR, A-I, Adenosine-to-Inosine RNA editing; NOTCH, Notch receptor; MYC, m proto-oncogene; miR, microRNA; MYOD, myogenic differentiation 1; THOC5, THO complex 5
Figure 5:
Figure 5:. Post-transcriptional regulatory mechanisms in the cytoplasm that control stem cell quiescence.
The mature mRNA can be degraded by miRNA-containing RISC complexes or RNA binding proteins (RBPs) with RNAse activity like TTP, stored in granules like DDX6-containing p-bodies, or translated by ribosomes. Translation can be regulated by RNA binding proteins like STAU1 (Staufen 1) or by mTORC signaling, and by phosphorylation of eIF2a. DDX6, DEAD-box helicase 6; MYF5, myogenic factor 5; miR, microRNA; 3’UTR, 3’ untranslated region; DICER, double-stranded RNA-specific endoribonuclease; RISC, RNA-induced silencing complex; RBP, RNA-binding protein; MyoD, myogenic differentiation 1; HNRNPD, heterogeneous nuclear ribonucleoprotein D; MMP9, matrix metallopeptidase 9; YTHDF2, YTH N6-methyladenosine RNA binding protein 2; TAL1, T-cell acute lymphocytic leukemia protein 1; PDCD4, programmed cell death 4; DEK, DEK proto-oncogene; TNS3, tensin 3; CCND2, cyclin d2; CDC25A,B, cell division cycle 25a,b; NLE1, notchless homolog 1; eIF2a, eukaryotic translation initiation factor 2A; MSI, musashi RNA binding protein 1; SSH, slingshot protein phosphatase; PAX3, paired box 3; AGO2, argonaute 2; mTOR1, mammalian target of rapamycin 1; MFGE8, milk fat globule EGF and factor V/VIII domain containing; FOXO3, forkhead box o3; AKT, AKT serine/threonine kinase, also known as protein kinase b.
Figure 6:
Figure 6:. Post-translational regulatory mechanisms that control stem cell quiescence.
Once translated, the native protein can be modified with post-translational modifications such as phosphorylation, glycosylation, and ubiquitination, which affect protein function and turnover. Ubiquitinated proteins can be degraded by the proteasome and the lysosome. FBW7, f-box and WD repeat domain containing 7; MYC, MYC proto-oncogene; Ub, ubiquitin; MAEA, macrophage erythroblast attacher; LRIG, leucine rich repeats and immunoglobulin like domains; EGFR, epidermal growth factor receptor; ID4, inhibitor of DNA binding 4; ASCL1, achaete-scute family BHLH transcription factor 1; SIRT7, sirtuin 7; NFATC1, nuclear factor of activated T Cells 1; HUWE1, HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1.
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