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First Isolation of Human Skeletal Stem Cells: The Key to Regenerative Approaches for Skeletal Disorder Treatment?

Review of “Identification of the Human Skeletal Stem Cell” from Cell by Stuart P. Atkinson 

Recent lineage-tracing and clonal analysis studies provided evidence for the existence of a mouse skeletal stem cell (mSSC) that exhibits the exclusive ability to generate bone, cartilage, and bone marrow stroma [1-3]. However, the relative absence of reliable cell-surface markers and related protocols and assays has hampered the discovery of putative human SSCs (hSSCs).

However, researchers from the laboratory of Michael T. Longaker (Stanford Medicine, Stanford, CA, USA) have published a new article in Cell in which they describe the isolation, regenerative activity, and cross-species comparison of a self-renewing hSSC with bone, cartilage, and stroma differentiation potential [4]. Is this new study by Chan et al. the key to regenerative approaches for skeletal disorder treatment? 

The authors first employed single-cell transcriptome analysis in mouse to compare areas of long bones undergoing skeletogenesis (epiphyseal or growth plate) with areas lacking skeletogenic activity (diaphysis, the main or midsection of a long bone) to provide clues to the cell-surface markers that may be required to purify hSSCs. This in-depth analysis uncovered a combination of four markers (PDPN+/CD146-/CD73+/CD164+) that permitted the selection of self-renewing multipotent hSSCs from fetal and adult bones, BMP2-treated human adipose stroma, and differentiating induced pluripotent stem cells (iPSCs). Selected hSSCs displayed the ability to generate progenitors of bone, cartilage, and bone marrow stroma upon subrenal transplantation in mouse, they failed to form fat progenitors. Specifically, hSSCs transit into an early bone, cartilage, and stroma progenitor (hBCSP) that subsequently gives rise to osteoprogenitors and chondroprogenitors before terminal differentiation. To assess functionality, the authors employed a human bone xenograft mouse model to prove that hSSCs underwent localized expansion in response to skeletal injury (unicortical fracture), and serum-free conditions to reveal that hSSCs supported the hematopoietic reconstitution abilities of human hematopoietic stem cells (hHSCs).

Subsequent gene expression analysis highlighted the general similarities but distinct nature of hSSCs obtained from different sources, while epigenetic and transcriptomic comparisons between mouse and human SSCs highlighted evolutionary similarities and differences in skeletogenesis. The high levels of expression of the SOST and DNAJB6 genes, linked to larger ossicle formation, and the associated faster cell growth of hSSCs when compared to mSSCs exemplifies these differences and, together, suggest that intrinsic mechanisms regulate skeletogenesis. 

The authors anticipate that their exciting discovery will permit additional in-depth characterization of both hSSCs and hSSC-derived skeletal progenitors to aid the diagnosis and reversal of skeletal disorders in a patient-specific manner as well as contributing to novel regenerative therapies.

For more on the human skeletal stem cell and future regenerative approaches for skeletal disorder treatment, stay tuned to the Stem Cells Portal

References

  1. Chan Charles KF, Seo Eun Y, Chen James Y, et al., Identification and Specification of the Mouse Skeletal Stem Cell. Cell 2015;160:285-298
  2. Marecic O, Tevlin R, McArdle A, et al., Identification and characterization of an injury-induced skeletal progenitor. Proceedings of the National Academy of Sciences 2015;112:9920-9925.
  3. Worthley Daniel L, Churchill M, Compton Jocelyn T, et al., Gremlin 1 Identifies a Skeletal Stem Cell with Bone, Cartilage, and Reticular Stromal Potential. Cell 2015;160:269-284.
  4. Chan CKF, Gulati GS, Sinha R, et al., Identification of the Human Skeletal Stem Cell. Cell 2018;175:43-56 e21.