Differential regulation of skeletal stem/progenitor cells in distinct skeletal compartments

Abstract

Skeletal stem/progenitor cells (SSPCs), characterized by self-renewal and multipotency, are essential for skeletal development, bone remodeling, and bone repair. These cells have traditionally been known to reside within the bone marrow, but recent studies have identified the presence of distinct SSPC populations in other skeletal compartments such as the growth plate, periosteum, and calvarial sutures. Differences in the cellular and matrix environment of distinct SSPC populations are believed to regulate their stemness and to direct their roles at different stages of development, homeostasis, and regeneration; differences in embryonic origin and adjacent tissue structures also affect SSPC regulation. As these SSPC niches are dynamic and highly specialized, changes under stress conditions and with aging can alter the cellular composition and molecular mechanisms in place, contributing to the dysregulation of local SSPCs and their activity in bone regeneration. Therefore, a better understanding of the different regulatory mechanisms for the distinct SSPCs in each skeletal compartment, and in different conditions, could provide answers to the existing knowledge gap and the impetus for realizing their potential in this biological and medical space. Here, we summarize the current scientific advances made in the study of the differential regulation pathways for distinct SSPCs in different bone compartments. We also discuss the physical, biological, and molecular factors that affect each skeletal compartment niche. Lastly, we look into how aging influences the regenerative capacity of SSPCs. Understanding these regulatory differences can open new avenues for the discovery of novel treatment approaches for calvarial or long bone repair.

Alexander Friedenstein, Mesenchymal Stem Cells, Shifting Paradigms and Euphemisms

“…In the 1980s, Owen and Friedenstein proposed using lineage tracing with genetic markers to verify the stem cell nature of marrow resident osteogenic precursors. As anticipated, this approach successfully identified several candidate skeletal stem/progenitor cell (SSPC) populations, including Nestin + [ 20 ] and LepR + [ 21 ] cells, while more recent studies combining lineage tracing with single cell RNA-based sequencing identified additional SSPCs in bone marrow, the growth plate, the periosteum, and calvarial sutures [ 22 ]. It is also well established that SSPCs resident in bone marrow secrete cytokines/chemokines that govern the retention and maintenance of HSCs [ 23 ].…”

The Mechanotransduction Signaling Pathways in the Regulation of Osteogenesis

“…Osteogenesis, the process of bone development and formation, is crucial to maintain the skeletal system [ 15 ]. Osteogenesis is involved in the process of bone remodeling and the subsequent repair of bone fractures [ 16 , 17 ]. Osteogenesis is tightly regulated by mechanical and biochemical signaling pathways [ 18 ].…”

“…Osteogenesis is tightly regulated by mechanical and biochemical signaling pathways [ 18 ]. During osteogenesis, the sequential differentiation occurs in osteoblast lineage cells, including mesenchymal stem cells (MSCs), osteoprogenitors, pre-osteoblasts, osteoblasts, and osteocytes [ 16 , 17 , 19 , 20 , 21 , 22 ]. Osteoblasts secrete the organic matrix osteoid, which is subsequently calcified to form the bone.…”

Dental Pulp Stem Cells and Current in vivo Approaches to Study Dental Pulp Stem Cells in Pulp Injury and Regeneration

“…[46] This suggests that Prrx1 + cells are important in tooth development and represent a dental stem/progenitor population, similar to Prrx1 + stem cells present in the long bone periosteum and calvarial suture. [47][48][49] Lastly, αSMA-green fluorescent protein (GFP) transgenic mice showed the presence of GFP + cells in the molar and incisor dental pulp from P7 to 6 weeks of age. These cells express Sca1 (a MSC marker) and are involved in odontogenesis during growth and development.…”