Skeletal Stem Cell Biology




Skeletal Stem Cell Biology
Injury and disease of skeletal tissue including bone and cartilage is an enormous, and growing medical burden. Our group has recently identified a self-renewing skeletal stem cell (mSSC) in mice that generates bone, cartilage and hematopoietic-supportive niche stromal cells (Cell, 2015). We then molecularly characterized the stem cell micro-environment (niche) of mSSC and identified specific signaling pathways guiding SSC expansion and differentiation towards bone or cartilage lineages. Through the lens of SSC biology, we observe that normal SSC activity is essential for normal skeletal homeostasis and regeneration (PNAS, 2015) while diminished or defective SSC activity underlies osteoporosis in aging and poor fracture healing in Type2 Diabetes Mellitus (STM, 2017). These studies define a pressing clinical need for identifying new methods to amplify SSC numbers and SSC activity in treating injuries or diseases of the skeletal system.
Furthermore, our research has also shown that a resident stem cell population can be induced to generate cartilage for treatment of localized chondral disease in OA mouse moudels (Nat. Med 2020) To speed clinical translation for our findings on mSSC, we have now succeeded in isolating and purifying human skeletal stem cells (hSSC) that are the functional equivalent of mouse SSC.
Through the lens of SSC biology, we observe that normal SSC activity is essential for normal skeletal homeostasis and regeneration (PNAS, 2015) while diminished or defective SSC activity underlies osteoporosis in aging and poor fracture healing in Type2 Diabetes Mellitus (STM, 2017). These studies define a pressing clinical need for identifying new methods to amplify SSC numbers and SSC activity in treating injuries or diseases of the skeletal system. To speed clinical translation for our findings on mSSC, we have now successfully isolated and purified human skeletal stem cells (hSSC) that are the functional equivalent of mouse SSC (Cell, 2018).
As we demonstrated in mice, we have also identified conditions for inducing human SSC and human bone and cartilage formation from human adipose tissue. Inducing SSC formation in situ with soluble factors and subsequently regulating the SSC niche to specify its differentiation towards bone, cartilage, or stromal cells would represent a paradigm shift in the therapeutic regeneration of skeletal tissues. Conversely, it is important to characterize the biology of SSC inducible cells and their potential role in pathological heterotropic ossification. This research seeks to address key questions regarding the identify of the SSC inducible cells present in human adipose tissue and the genetic mechanisms underlying plasticity in their cell fates and the process of re-specification into induced SSCs (iSSCs). We are also examining the biological differences between iSSCs and endogenous SSCs isolated from skeletal tissues in response to signaling that promote expansion and lineage commitment of SSC.
Through the lens of SSC biology, we observe that normal SSC activity is essential for normal skeletal homeostasis and regeneration (PNAS, 2015) while diminished or defective SSC activity underlies osteoporosis in aging and poor fracture healing in Type2 Diabetes Mellitus (STM, 2017). These studies define a pressing clinical need for identifying new methods to amplify SSC numbers and SSC activity in treating injuries or diseases of the skeletal system. To speed clinical translation for our findings on mSSC, we have now successfully isolated and purified human skeletal stem cells (hSSC) that are the functional equivalent of mouse SSC (Cell, 2018).
As we demonstrated in mice, we have also identified conditions for inducing human SSC and human bone and cartilage formation from human adipose tissue. Inducing SSC formation in situ with soluble factors and subsequently regulating the SSC niche to specify its differentiation towards bone, cartilage, or stromal cells would represent a paradigm shift in the therapeutic regeneration of skeletal tissues. Conversely, it is important to characterize the biology of SSC inducible cells and their potential role in pathological heterotropic ossification. This research seeks to address key questions regarding the identify of the SSC inducible cells present in human adipose tissue and the genetic mechanisms underlying plasticity in their cell fates and the process of re-specification into induced SSCs (iSSCs). We are also examining the biological differences between iSSCs and endogenous SSCs isolated from skeletal tissues in response to signaling that promote expansion and lineage commitment of SSC.

As we demonstrated in mice, we have also identified conditions for inducing human SSC and human bone and cartilage formation from human adipose tissue. Inducing SSC formation in situ with soluble factors and subsequently regulating the SSC niche to specify its differentiation towards bone, cartilage, or stromal cells would represent a paradigm shift in the therapeutic regeneration of skeletal tissues. Conversely, it is important to characterize the biology of SSC inducible cells and their potential role in pathological heterotropic ossification. This research seeks to address key questions regarding the identify of the SSC inducible cells present in human adipose tissue and the genetic mechanisms underlying plasticity in their cell fates and the process of re-specification into induced SSCs (iSSCs). We are also examining the biological differences between iSSCs and endogenous SSCs isolated from skeletal tissues in response to signaling that promote expansion and lineage commitment of SSC.
Selected Publications
Selected Publications
1. Menon S, Salhotra A, Shailendra S, Tevlin R, Ransom RC, Januszyk M, Chan CKF, Behr B, Wan DC, Longaker MT, Quarto N. Skeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis. Nat Commun. 2021 Jul 30;12(1):4640. doi: 10.1038/s41467-021-24801-6. PMID: 34330896; PMCID: PMC8324898.
2. Articular cartilage regeneration by activated skeletal stem cells. Murphy MP, Koepke LS, Lopez MT, Tong X, Ambrosi TH, Gulati GS, Marecic O, Wang Y, Ransom RC, Hoover MY, Steininger H, Zhao L, Walkiewicz MP, Quarto N, Levi B, Wan DC, Weissman IL, Goodman SB, Yang F, Longaker MT, Chan CKF. Nat Med. 2020 Oct;26(10):1583-1592. doi: 10.1038/s41591-020-1013-2.
3. Identification of the Human Skeletal Stem Cell. Chan CKF, Gulati GS, Sinha R, Tompkins JV, Lopez M, Carter AC, Ransom RC, Reinisch A, Wearda T, Murphy M, Brewer RE, Koepke LS, Marecic O, Manjunath A, Seo EY, Leavitt T, Lu WJ, Nguyen A, Conley SD, Salhotra A, Ambrosi TH, Borrelli MR, Siebel T, Chan K, Schallmoser K, Seita J, Sahoo D, Goodnough H, Bishop J, Gardner M, Majeti R, Wan DC, Goodman S, Weissman IL, Chang HY, Longaker MT. Cell. 2018 Sep 20;175(1):43-56.e21. doi: 10.1016/j.cell.2018.07.029.
4. Pharmacological rescue of diabetic skeletal stem cell niches. Tevlin R, Seo EY, Marecic O, McArdle A, Tong X, Zimdahl B, Malkovskiy A, Sinha R, Gulati G, Li X, Wearda T, Morganti R, Lopez M, Ransom RC, Duldulao CR, Rodrigues M, Nguyen A, Januszyk M, Maan Z, Paik K, Yapa KS, Rajadas J, Wan DC, Gurtner GC, Snyder M, Beachy PA, Yang F, Goodman SB, Weissman IL, Chan CK, Longaker MT. Sci Transl Med. 2017 Jan 11;9(372):eaag2809. doi: 10.1126/scitranslmed.aag2809.
5. Chan CK, Seo EY, Chen JY, Lo D, McArdle A, Sinha R, Tevlin R, Seita J, Vincent-Tompkins J, Wearda T, Lu WJ, Senarath-Yapa K, Chung MT, Marecic O, Tran M, Yan KS, Upton R, Walmsley GG, Lee AS, Sahoo D, Kuo CJ, Weissman IL, Longaker MT. Identification and specification of the mouse skeletal stem cell. Cell. 2015 Jan 15;160(1-2):285-98. doi: 10.1016/j.cell.2014.12.002.
6. Marecic O, Tevlin R, McArdle A, Seo EY, Wearda T, Duldulao C, Walmsley GG, Nguyen A, Weissman IL, Chan CK, Longaker MT. Identification and characterization of an injury-induced skeletal progenitor. Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):9920-5. doi: 10.1073/pnas.1513066112. Epub 2015 Jul 27. PMID: 26216955
Selected Publications