Distinct skeletal stem cell types orchestrate long bone skeletogenesis

Abstract

Skeletal stem and progenitor cell populations are crucial for bone physiology. Characterization of these cell types remains restricted to heterogenous bulk populations with limited information on whether they are unique or overlap with previously characterized cell types. Here we show, through comprehensive functional and single-cell transcriptomic analyses, that postnatal long bones of mice contain at least two types of bone progenitors with bona fide skeletal stem cell (SSC) characteristics. An early osteochondral SSC (ocSSC) facilitates long bone growth and repair, while a second type, a perivascular SSC (pvSSC), co-emerges with long bone marrow and contributes to shape the hematopoietic stem cell niche and regenerative demand. We establish that pvSSCs, but not ocSSCs, are the origin of bone marrow adipose tissue. Lastly, we also provide insight into residual SSC heterogeneity as well as potential crosstalk between the two spatially distinct cell populations. These findings comprehensively address previously unappreciated shortcomings of SSC research.

The Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase Pathway in Osteoblasts

“…Whereas a decade or more ago, the cells comprising bone were largely categorized in terms of simple morphologic and functional characteristics into chondrocytes, osteoblasts, and osteocytes, a much richer picture has emerged in recent work of many specific cell types and lineages that are discriminated through cell surface markers or genetic lineage reporters. These cell types include PTHrP + growth plate-resident stem cells,[ 26 ] specific periosteal stem cells,[ 29 , 85 ] FACS defined skeletal stem cells that include populations both overlapping and not overlapping with these 2 former cell types,[ 113 – 115 ] ACTA2-lineage osteoprogenitors,[ 116 ] and multiple subsets of CXCL12-abundant reticular cells that comprise the marrow stroma,[ 30 , 31 ] many of which also express LEPR. [ 32 , 117 ] This discovery of an increasingly diversifying set of skeletal cell types is the important challenge that it is no longer sufficient to simply define how a given signaling pathway augments or inhibits osteoblast differentiation.…”

WHIM Syndrome-linked CXCR4 mutations drive osteoporosis by mitigating the osteogenic specification of skeletal stromal cells

“…Further studies are required to address the status of Ebf3 and downstream target genes that act to modulate osteogenic fate of SSCs in Cxcr4 1013 -bearing mice. A potential crosstalk between distinct SSC subsets, either prone to differentiate into osteochondro-lineage cells or perivascular and adipocyte lineage cells, has been reported 67 . This seems to imply ligand-receptor gene pairs such as TGFb, WNT or BMP ligands and their cognate receptors that regulate SSC fate decision.…”

EXTENSIVE EXPERTISE IN ENDOCRINOLOGY: My quarter century quest to understand the paradox of marrow adiposity

“…Back at Yale, Mark Horowitz was using lineage tracing studies to ascertain their origin, and in combination with the MacDougald group, began to get traction. Work by Sean Morrison and others had identified markers of marrow adipocyte progenitors and this, combined with seminal studies from the Longaker laboratory, provided a strong foundation for more elaborate studies on the origin of those cells (26,27). Mark noted that osterix, or SP7, a gene critical for osteoblast differentiation, lineage traced not only to osteoblasts but also marrow adipocytes.…”