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Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence.
Stem Cells Transl Med. 2017 03; 6(3):799-806.SC

Abstract

Trauma-induced heterotopic ossification (HO) occurs after severe musculoskeletal injuries and burns, and presents a significant barrier to patient rehabilitation. Interestingly, the incidence of HO significantly increases with repeated operations and after resection of previous HO. Treatment of established heterotopic ossification is challenging because surgical excision is often incomplete, with evidence of persistent heterotopic bone. As a result, patients may continue to report the signs or symptoms of HO, including chronic pain, nonhealing wounds, and joint restriction. In this study, we designed a model of recurrent HO that occurs after surgical excision of mature HO in a mouse model of hind-limb Achilles' tendon transection with dorsal burn injury. We first demonstrated that key signaling mediators of HO, including bone morphogenetic protein signaling, are diminished in mature bone. However, upon surgical excision, we have noted upregulation of downstream mediators of osteogenic differentiation, including pSMAD 1/5. Additionally, surgical excision resulted in re-emergence of a mesenchymal cell population marked by expression of platelet-derived growth factor receptor-α (PDGFRα) and present in the initial developing HO lesion but absent in mature HO. In the recurrent lesion, these PDGFRα+ mesenchymal cells are also highly proliferative, similar to the initial developing HO lesion. These findings indicate that surgical excision of HO results in recurrence through similar mesenchymal cell populations and signaling mechanisms that are present in the initial developing HO lesion. These results are consistent with findings in patients that new foci of ectopic bone can develop in excision sites and are likely related to de novo formation rather than extension of unresected bone. Stem Cells Translational Medicine 2017;6:799-806.

Authors+Show Affiliations

Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.Burn/Wound and Regenerative Medicine Laboratory, Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28297577

Citation

Agarwal, Shailesh, et al. "Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence." Stem Cells Translational Medicine, vol. 6, no. 3, 2017, pp. 799-806.
Agarwal S, Loder S, Cholok D, et al. Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence. Stem Cells Transl Med. 2017;6(3):799-806.
Agarwal, S., Loder, S., Cholok, D., Li, J., Breuler, C., Drake, J., Brownley, C., Peterson, J., Li, S., & Levi, B. (2017). Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence. Stem Cells Translational Medicine, 6(3), 799-806. https://doi.org/10.5966/sctm.2015-0365
Agarwal S, et al. Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence. Stem Cells Transl Med. 2017;6(3):799-806. PubMed PMID: 28297577.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence. AU - Agarwal,Shailesh, AU - Loder,Shawn, AU - Cholok,David, AU - Li,John, AU - Breuler,Chris, AU - Drake,James, AU - Brownley,Cameron, AU - Peterson,Joshua, AU - Li,Shuli, AU - Levi,Benjamin, Y1 - 2016/10/05/ PY - 2015/11/23/received PY - 2016/08/29/accepted PY - 2017/3/16/entrez PY - 2017/3/16/pubmed PY - 2019/7/6/medline KW - Bone KW - Chondrogenesis KW - Extremity trauma KW - Heterotopic ossification KW - Mesenchymal stem cell KW - Tissue regeneration SP - 799 EP - 806 JF - Stem cells translational medicine JO - Stem Cells Transl Med VL - 6 IS - 3 N2 - Trauma-induced heterotopic ossification (HO) occurs after severe musculoskeletal injuries and burns, and presents a significant barrier to patient rehabilitation. Interestingly, the incidence of HO significantly increases with repeated operations and after resection of previous HO. Treatment of established heterotopic ossification is challenging because surgical excision is often incomplete, with evidence of persistent heterotopic bone. As a result, patients may continue to report the signs or symptoms of HO, including chronic pain, nonhealing wounds, and joint restriction. In this study, we designed a model of recurrent HO that occurs after surgical excision of mature HO in a mouse model of hind-limb Achilles' tendon transection with dorsal burn injury. We first demonstrated that key signaling mediators of HO, including bone morphogenetic protein signaling, are diminished in mature bone. However, upon surgical excision, we have noted upregulation of downstream mediators of osteogenic differentiation, including pSMAD 1/5. Additionally, surgical excision resulted in re-emergence of a mesenchymal cell population marked by expression of platelet-derived growth factor receptor-α (PDGFRα) and present in the initial developing HO lesion but absent in mature HO. In the recurrent lesion, these PDGFRα+ mesenchymal cells are also highly proliferative, similar to the initial developing HO lesion. These findings indicate that surgical excision of HO results in recurrence through similar mesenchymal cell populations and signaling mechanisms that are present in the initial developing HO lesion. These results are consistent with findings in patients that new foci of ectopic bone can develop in excision sites and are likely related to de novo formation rather than extension of unresected bone. Stem Cells Translational Medicine 2017;6:799-806. SN - 2157-6564 UR - https://www.unboundmedicine.com/medline/citation/28297577/Surgical_Excision_of_Heterotopic_Ossification_Leads_to_Re_Emergence_of_Mesenchymal_Stem_Cell_Populations_Responsible_for_Recurrence_ L2 - https://doi.org/10.5966/sctm.2015-0365 DB - PRIME DP - Unbound Medicine ER -