New perspective of skeletal stem cells

Abstract

Tissue-resident stem cells are a group of stem cells distinguished by their capacity for self-renewal and multilineage differentiation capability with tissue specificity. Among these tissue-resident stem cells, skeletal stem cells (SSCs) were discovered in the growth plate region through a combination of cell surface markers and lineage tracing series. With the process of unravelling the anatomical variation of SSCs, researchers were also keen to investigate the developmental diversity outside the long bones, including in the sutures, craniofacial sites, and spinal regions. Recently, fluorescence-activated cell sorting, lineage tracing, and single-cell sequencing have been used to map lineage trajectories by studying SSCs with different spatiotemporal distributions. The SSC niche also plays a pivotal role in regulating SSC fate, such as cell-cell interactions mediated by multiple signalling pathways. This review focuses on discussing the spatial and temporal distribution of SSCs, and broadening our understanding of the diversity and plasticity of SSCs by summarizing the progress of research into SSCs in recent years.

Keywords: bone repair; endochondral ossification; growth plate; lineage tracing; skeletal stem cells.

Figure 1. The distribution of SSCs in the growth plate, periosteum, bone marrow, and peripheral circulation shows different cell surface markers. The cell surface markers of SSCs on the growth plate are CD200⁺, PTHrP⁺ Col2a1⁺, Gli1⁺, FoxA2⁺, and mTert⁺. The cell surface markers of PSCs are Ctsk⁺, Prx1⁺ Axin2⁺, Sox9⁺, Mx1⁺, and α-SMA⁺. The cell surface markers of SSCs in the bone marrow cavity are Lepr⁺, Nestin⁺, Nes⁺, Cxcl12⁺, and Grem1⁺. The cell surface markers of circulating osteogenic cells in the peripheral circulation are haematopoietic COP cells (CD45⁺, CD34⁺, CD14⁺, OCN⁺, AP⁺, and Col1⁺) and MSC-like COP cells (CD45–, CD34–, CD44⁺, CD73⁺, CD90⁺, and CD105⁺). Axin2: axis inhibition protein 2; AP: alkaline phosphatase; OCN: osteocalcin; Col1: type 1 collagen; Col2a1: type 2 collagen alpha 1 chain; COP: circulating osteogenic cell; Ctsk: cathepsin K; Cxcl12: chemokine (C-X-C motif) ligand 12; FoxA2: forkhead box A2; Gli1: GLI-Kruppel family member GLI1; Grem1: gremlin 1, DAN family BMP antagonist; Lepr: leptin receptor; MSC: mesenchymal stem cell; mTert: mouse Telomerase; Mx1: MX dynamin like GTPase 1; Nes: nestin; Prx1: paired related homeobox 1; PSC: periosteal stem cell; PTHrP: parathyroid-associated protein; Sox9: SRY (sex determining region Y)-box 9; SSCs: skeletal stem cells; α-SMA: α-smooth muscle actin.

Figure 2. Distribution of SSCs in craniofacial bone, with different cell surfaces shown. The cell surface markers of SSCs in the cranial periosteum are Ctsk⁺ and Mx1⁺αSMA⁺. The cell surface markers of SSCs in the calvarial sutures are Gli1⁺, Prx1⁺, and Axin2⁺. The cell surface markers of SSCs in the teeth and periodontal tissue are Gli1⁺, Prx1⁺, and Axin2⁺. The cell surface markers of SSCs in the jaw bone are Ctsk⁺ and Ly6a⁺. Axin2: axis inhibition protein 2; Ctsk: cathepsin K; Gli1: GLI-Kruppel family member GLI1; Ly6a: lymphocyte antigen 6 complex, locus A; Mx1: MX dynamin like GTPase 1; Prx1: paired related homeobox 1; SSC: skeletal stem cell; αSMA: α-smooth muscle actin.

Figure 3. Circulating osteogenic cells contribute to bone formation through stem cell homing to receive IGF-1, PDGF- AB, SDF-1, and MDC. M-CSF stimulates HSCs to differentiate into monocytes and macrophages and then differentiate into osteoclasts to receive RANKL. COP: circulating osteogenic precursor cell; HSC: haematopoietic stem cell; IGF-1: insulin-like growth factor 1; M-CSF: macrophage colony-stimulating factor; MDC: macrophage-derived chemokine; MSC: mesenchymal stem cell; PDGF-AB: platelet derived growth factor AB; RANKL: receptor activator of nuclear factor kappa-? ligand; SDF-1: stromal cell-derived factor-1.

Figure 4. (A) Wnt and BMP2 are enriched in PSCs. PDGF-BB and CCL5/CCR3/CCR5 promote the migration of SSCs, while activation of Piezo1 promotes the expression and nuclear localisation of Yap in PSCs, and forms a transcriptional Yap/β-catenin complex which promotes fracture healing. (B) The Wnt and mTORC1 signalling pathways regulate SSCs of the growth plate. PSCs control growth plate SSCs through the Ihh signalling pathway. (C) Aged mice develop a pro-inflammatory microenvironment that disrupts the osteoclast–osteoblast balance. A combination of BMP2 and CSF1 antagonists reverses this change and activates aging SSCs in mice, returning them to a younger state. BMP2: bone morphogenetic protein 2; CCL5: chemokine (C-C motif) ligand 5; CCR3: C-C motif chemokine receptor 3; CCR5: C-C motif chemokine receptor 5; CSF1: colony stimulating factor 1; mTORC1: mechanistic target of rapamycin complex; PDGF-BB: platelet derived growth factor BB; PSC: periosteal stem cell; PTHrP: parathyroid hormone-related protein; Wnt: wingless-related integration site; Yap: yes-related protein.