Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization

Madysen K. Hunter; Sneha Korlakunta; Neda Vishlaghi; Monisha Mittal; Kyle Cragg; Conan Juan; Chase A. Pagani; Yuxiao Sun; Lindsey Lammlin; Karen Kessell; Dylan Feist; Ji Hae Choi; Meng Lun Hsieh; Jahnu Saikia; Craig L. Duvall; Heeseog Kang; Andrea I. Alford; Kurt D. Hankenson; Robert J. Tower; Tristan Maerz; Benjamin Levi

doi:10.1038/s41413-025-00493-2

Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization

Madysen K. Hunter, Sneha Korlakunta, Neda Vishlaghi, Monisha Mittal, Kyle Cragg, Conan Juan, Chase A. Pagani, Yuxiao Sun, Lindsey Lammlin, Karen Kessell, Dylan Feist, Ji Hae Choi, Meng Lun Hsieh, Jahnu Saikia, Craig L. Duvall, Heeseog Kang, Andrea I. Alford, Kurt D. Hankenson, Robert J. Tower, Tristan MaerzBenjamin Levi^*

^*Corresponding author for this work

Surgery

Research output: Contribution to journal › Article › peer-review

Abstract

Thrombospondin 1 and 2 (TSP1 and TSP2) are critical regulators of extracellular matrix (ECM) interactions, influencing cell differentiation and tissue repair. Recent discoveries from our laboratory and others highlight the importance of altered ECM alignment in influencing aberrant mesenchymal progenitor cell (MPC) differentiation and subsequent ectopic bone formation in trauma-induced heterotopic ossification (HO). However, the key regulators of this MPC to ECM interaction have yet to be elucidated. This study uncovers the role of matricellular TSP1 and TSP2 in MPC/ECM interaction as well as HO formation and progression. Using single-cell RNA sequencing, spatial transcriptomics, and in vivo models, we found that TSP1 is upregulated in tissue remodeling macrophages and MPCs at the injury site, while TSP2 is restricted to MPCs surrounding the HO anlagen. TSP1/2 double knockout (DKO) mice exhibited significantly reduced HO volume and disrupted ECM alignment. These findings highlight the crucial roles of TSP1 and TSP2 in musculoskeletal injury repair as well as HO formation and progression, supporting the potential to therapeutically target TSP1 and TSP2 to prevent HO.

Original language	English
Article number	10
Journal	Bone Research
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41413-025-00493-2
State	Published - Dec 2026

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Hunter, M. K., Korlakunta, S., Vishlaghi, N., Mittal, M., Cragg, K., Juan, C., Pagani, C. A., Sun, Y., Lammlin, L., Kessell, K., Feist, D., Choi, J. H., Hsieh, M. L., Saikia, J., Duvall, C. L., Kang, H., Alford, A. I., Hankenson, K. D., Tower, R. J., ... Levi, B. (2026). Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization. Bone Research, 14(1), Article 10. https://doi.org/10.1038/s41413-025-00493-2

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title = "Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization",

abstract = "Thrombospondin 1 and 2 (TSP1 and TSP2) are critical regulators of extracellular matrix (ECM) interactions, influencing cell differentiation and tissue repair. Recent discoveries from our laboratory and others highlight the importance of altered ECM alignment in influencing aberrant mesenchymal progenitor cell (MPC) differentiation and subsequent ectopic bone formation in trauma-induced heterotopic ossification (HO). However, the key regulators of this MPC to ECM interaction have yet to be elucidated. This study uncovers the role of matricellular TSP1 and TSP2 in MPC/ECM interaction as well as HO formation and progression. Using single-cell RNA sequencing, spatial transcriptomics, and in vivo models, we found that TSP1 is upregulated in tissue remodeling macrophages and MPCs at the injury site, while TSP2 is restricted to MPCs surrounding the HO anlagen. TSP1/2 double knockout (DKO) mice exhibited significantly reduced HO volume and disrupted ECM alignment. These findings highlight the crucial roles of TSP1 and TSP2 in musculoskeletal injury repair as well as HO formation and progression, supporting the potential to therapeutically target TSP1 and TSP2 to prevent HO.",

author = "Hunter, {Madysen K.} and Sneha Korlakunta and Neda Vishlaghi and Monisha Mittal and Kyle Cragg and Conan Juan and Pagani, {Chase A.} and Yuxiao Sun and Lindsey Lammlin and Karen Kessell and Dylan Feist and Choi, {Ji Hae} and Hsieh, {Meng Lun} and Jahnu Saikia and Duvall, {Craig L.} and Heeseog Kang and Alford, {Andrea I.} and Hankenson, {Kurt D.} and Tower, {Robert J.} and Tristan Maerz and Benjamin Levi",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = dec,

doi = "10.1038/s41413-025-00493-2",

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Hunter, MK, Korlakunta, S, Vishlaghi, N, Mittal, M, Cragg, K, Juan, C, Pagani, CA, Sun, Y, Lammlin, L, Kessell, K, Feist, D, Choi, JH, Hsieh, ML, Saikia, J, Duvall, CL, Kang, H, Alford, AI, Hankenson, KD, Tower, RJ, Maerz, T & Levi, B 2026, 'Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization', Bone Research, vol. 14, no. 1, 10. https://doi.org/10.1038/s41413-025-00493-2

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AU - Hunter, Madysen K.

AU - Korlakunta, Sneha

AU - Vishlaghi, Neda

AU - Mittal, Monisha

AU - Cragg, Kyle

AU - Juan, Conan

AU - Pagani, Chase A.

AU - Sun, Yuxiao

AU - Lammlin, Lindsey

AU - Kessell, Karen

AU - Feist, Dylan

AU - Choi, Ji Hae

AU - Hsieh, Meng Lun

AU - Saikia, Jahnu

AU - Duvall, Craig L.

AU - Kang, Heeseog

AU - Alford, Andrea I.

AU - Hankenson, Kurt D.

AU - Tower, Robert J.

AU - Maerz, Tristan

AU - Levi, Benjamin

PY - 2026/12

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N2 - Thrombospondin 1 and 2 (TSP1 and TSP2) are critical regulators of extracellular matrix (ECM) interactions, influencing cell differentiation and tissue repair. Recent discoveries from our laboratory and others highlight the importance of altered ECM alignment in influencing aberrant mesenchymal progenitor cell (MPC) differentiation and subsequent ectopic bone formation in trauma-induced heterotopic ossification (HO). However, the key regulators of this MPC to ECM interaction have yet to be elucidated. This study uncovers the role of matricellular TSP1 and TSP2 in MPC/ECM interaction as well as HO formation and progression. Using single-cell RNA sequencing, spatial transcriptomics, and in vivo models, we found that TSP1 is upregulated in tissue remodeling macrophages and MPCs at the injury site, while TSP2 is restricted to MPCs surrounding the HO anlagen. TSP1/2 double knockout (DKO) mice exhibited significantly reduced HO volume and disrupted ECM alignment. These findings highlight the crucial roles of TSP1 and TSP2 in musculoskeletal injury repair as well as HO formation and progression, supporting the potential to therapeutically target TSP1 and TSP2 to prevent HO.

AB - Thrombospondin 1 and 2 (TSP1 and TSP2) are critical regulators of extracellular matrix (ECM) interactions, influencing cell differentiation and tissue repair. Recent discoveries from our laboratory and others highlight the importance of altered ECM alignment in influencing aberrant mesenchymal progenitor cell (MPC) differentiation and subsequent ectopic bone formation in trauma-induced heterotopic ossification (HO). However, the key regulators of this MPC to ECM interaction have yet to be elucidated. This study uncovers the role of matricellular TSP1 and TSP2 in MPC/ECM interaction as well as HO formation and progression. Using single-cell RNA sequencing, spatial transcriptomics, and in vivo models, we found that TSP1 is upregulated in tissue remodeling macrophages and MPCs at the injury site, while TSP2 is restricted to MPCs surrounding the HO anlagen. TSP1/2 double knockout (DKO) mice exhibited significantly reduced HO volume and disrupted ECM alignment. These findings highlight the crucial roles of TSP1 and TSP2 in musculoskeletal injury repair as well as HO formation and progression, supporting the potential to therapeutically target TSP1 and TSP2 to prevent HO.

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