A Revised Perspective of Skeletal Stem Cell Biology

Abstract

Bone-related maladies are a major health burden on modern society. Loss of skeletal integrity and regeneration capacity through aging, obesity, and disease follows from a detrimental shift in bone formation and resorption dynamics. Targeting tissue-resident adult stem cells offers a potentially innovative paradigm in the development of therapeutic strategies against organ dysfunction. While the essential role of skeletal stem cells (SSCs) for development, growth, and maintenance of the skeleton has been generally established, a common consensus on the exact identity and definition of a pure bona fide SSC population remains elusive. The controversies stem from conflicting results between different approaches and criteria for isolation, detection, and functional evaluation; along with the interchangeable usage of the terms SSC and “mesenchymal stromal/stem cell (MSC)”. A great number of prospective bone-forming stem cell populations have been reported with various characteristic markers, often describing overlapping cell populations with widely unexplored heterogeneity, species specificity, and distribution at distinct skeletal sites, bone regions, and microenvironments, thereby creating confusion that may complicate future advances in the field. In this review, we examine the state-of-the-art knowledge of SSC biology and try to establish a common ground for the definition and terminology of specific bone-resident stem cells. We also discuss recent advances in the identification of highly purified SSCs, which will allow detailed interrogation of SSC diversity and regulation at the single-cell level.

Standardised Nomenclature, Abbreviations, and Units for the Study of Bone Marrow Adiposity: Report of the Nomenclature Working Group of the International Bone Marrow Adiposity Society

“…Nonetheless, the use of the term "SSC" is appropriate based on the retrospective evidence of stemness demonstrated by the generation of ossicles by clonal populations of BMSCs. However, it is important to note that other populations of SSCs have recently been identified in the growth plate and in the periosteum in both mice and humans, but it does not appear that SSCs from these origins contribute to BMA [reviewed in (123)] (104,(123)(124)(125)(126). Similarly, stromal cells capable of adipogenesis ex vivo have been isolated from cortical bone of the femoral diaphysis and cancellous/cortical bone of the proximal epiphysis of rats (127,128).…”

Single-cell RNA sequencing deconvolutes thein vivoheterogeneity of human bone marrow-derived mesenchymal stem cells

“…Human and mice BM-MSCs often present different cell surface markers 3 . Consistent with this result, by comparing the DEGs between hBM-MSCs and mBM-MSCs (Extended Data Fig.…”

“…Currently, the cells that give rise to osteoblast/osteocyte, chondrocyte, and adipocyte are generally referred to as "mesenchymal stromal/stem cells" (MSCs), which are non-hematopoietic bone marrow stromal cells with fibroblast colony-forming unit (CFU-F) and multi-differentiation capacity 2 . Typically, the human bone-marrow derived MSCs (BM-MSCs) are isolated with a combination of non-specific cell-surface markers such as high expression of CD271, CD44, CD105, CD73, CD90, and low expression/absent of CD45, CD34, CD14 or CD11b, CD79a or CD19, and human leukocyte antigen HLA-DR 3,4 . Among these markers, CD271 shows great efficiency to sort MSCs either alone or in combination with negative selection of markers such as CD45 5,6 .…”

Single cell RNA sequence analysis of human bone marrow samples reveals new targets for isolation of skeletal stem cells using DNA-coated gold nanoparticles

“…A sub-endothelial perivascular origin of the SSCs in bone marrow is widely acknowledged [3,[15][16][17]. To characterise the cellular heterogeneity within human adult bone marrow and to identify potential markers for SSC enrichment, scRNA-seq was performed, using the Drop-Seq methodology [9].…”