Bone marrow endosteal stem cells dictate active osteogenesis and aggressive tumorigenesis

Abstract

The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal cells contribute to a stem cell fraction in young stages, which is later replaced by Lepr-cre-marked stromal cells in adult stages. Further, Fgfr3+ endosteal stromal cells give rise to aggressive osteosarcoma-like lesions upon loss of p53 tumor suppressor through unregulated self-renewal and aberrant osteogenic fates. Therefore, Fgfr3+ endosteal SSCs are abundant in young bone marrow and provide a robust source of osteoblasts, contributing to both normal and aberrant osteogenesis.

Endosteal stem cells at the bone‐blood interface: A double‐edged sword for rapid bone formation

“…51 We performed scRNA-seq analyses of Prrx1-cre-labeled cells at 3 weeks old (Young) and 1.5 years old (Old) mice, and the Young and Old scRNA-seq datasets were computationally integrated by the LIGER algorithm. 12,52,53 Interestingly, this integrative scRNA-seq analysis identified a small population of bone marrow stromal cells that are almost exclusively present in young bone marrow. These cells are positioned in the middle of the three major cell types of osteoblasts, chondrocytes and preadipocyte-like reticular cells, and possess characteristics of both osteoblasts and chondrocytes (i.e., osteoblast-chondrocyte transitional "OCT" identities), expressing molecular markers of chondrocytes (e.g., Acan), osteoblasts (e.g., Col1a1) and reticular cells (e.g., Cxcl12) at a lower level than those of the canonical cell types.…”

“…These cells are positioned in the middle of the three major cell types of osteoblasts, chondrocytes and preadipocyte-like reticular cells, and possess characteristics of both osteoblasts and chondrocytes (i.e., osteoblast-chondrocyte transitional "OCT" identities), expressing molecular markers of chondrocytes (e.g., Acan), osteoblasts (e.g., Col1a1) and reticular cells (e.g., Cxcl12) at a lower level than those of the canonical cell types. 12 The next important question is whether these OCT cells in young bone marrow can behave as stem cells. Computational cell fate mapping provides a viable approach to identify putative stem cells of a given lineage.…”

“…Unique characteristics of skeletal stem cells residing in each sub-compartment are now beginning to be unraveled. [12][13][14] The endosteal space is a sub-compartment of the bone marrow that is near the bone surface, which provides a particularly important microenvironment for somatic stem cells, including skeletal and hematopoietic stem cells. The endosteal space is highly vascularized and innervated.…”

“…We have recently identified a new population of skeletal stem cells in the endosteal space, which are particularly abundant in young and growing bone marrow. 12 The identification of endosteal stem cells fills the gap in knowledge in skeletal stem cells, which contribute to bone formation in the transition between leptin receptor (LepR) + stromal cells in adult bone marrow which provide a steady source of osteoblasts toward aged stages 14 and hypertrophic chondrocytes in the growth plate that can transform into osteoblasts in early skeletal development. 24,25 Endosteal stem cells possess robust osteogenic capabilities and are different in characteristics from those identified in other compartments, such as periosteal stem cells (PSCs), [26][27][28] growth plate stem cells (GPSCs) 29,30 or adult bone marrow stromal stem cells (BMSCs).…”

Identification of the metaphyseal skeletal stem cell building trabecular bone

“…BMSCs exhibit varying progenitor properties, largely due to the fact that BMSCs may contain distinct SSC populations. Recent studies reveal that Fgfr3 + bone marrow endosteal stem cells and Lepr + Adiponectin + SSPCs contribute to osteogenesis in young and adult stages, respectively ( 23 , 24 ). However, the expression of most SSC markers spans other cell types.…”