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Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification.
Bone. 2018 04; 109:71-79.BONE

Abstract

Heterotopic ossification (HO), acquired or hereditary, endochondral or intramembranous, is the formation of true bone outside the normal skeleton. Since perivascular Gli1+ progenitors contribute to injury induced organ fibrosis, and CD133 is expressed by a variety of populations of adult stem cells, this study utilized Cre-lox based genetic lineage tracing to test the contribution to endochondral HO of adult stem/progenitor cells that expressed either Gli1 or CD133. We found that both lineages contributed broadly to different normal tissues with distinct patterns, but that only Gli1-creERT labeled stem/progenitor cells contributed to all stages of endochondral HO in a BMP dependent, injury induced, transgenic mouse model. Hedgehog (Hh) signaling was abnormal at endochondral HO lesion sites with increased signaling surrounding the lesion but diminished signaling within it. Thus, local dysregulation of Hh signaling participates in the pathophysiology of endochondral HO. However, unlike a previous report of intramembranous HO, systemic inhibition of Hh signaling was insufficient to prevent the initiation of the endochondral HO process or to treat the existing endochondral HO, suggesting that Hh participates in, but is not essential for endochondral HO in this model. This could potentially reflect the underlying difference between intramembranous and endochondral HO. Nevertheless, identification of this novel stem/precursor cell population as a HO-contributing cell population provides a potential drugable target.

Authors+Show Affiliations

School of Basic Medical Sciences, Anhui Medical University, 81 Meishan road, Hefei 230032, China.School of Basic Medical Sciences, Anhui Medical University, 81 Meishan road, Hefei 230032, China.School of Basic Medical Sciences, Anhui Medical University, 81 Meishan road, Hefei 230032, China.School of Basic Medical Sciences, Anhui Medical University, 81 Meishan road, Hefei 230032, China.Department of Medical Laboratory Science, Bengbu Medical College, 2600 Donghai Ave, Longzihu, Bengbu 233030, Anhui, China.Department of Neurology, Northwestern University, Ward Building 10-233, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA.School of Basic Medical Sciences, Anhui Medical University, 81 Meishan road, Hefei 230032, China.Department of Neurology, Northwestern University, Ward Building 10-233, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA.School of Basic Medical Sciences, Anhui Medical University, 81 Meishan road, Hefei 230032, China; Department of Medical Laboratory Science, Bengbu Medical College, 2600 Donghai Ave, Longzihu, Bengbu 233030, Anhui, China; Department of Neurology, Northwestern University, Ward Building 10-233, 303 East Chicago Avenue, Chicago, IL 60611-3008, USA. Electronic address: l-kan@northwstern.edu.

Pub Type(s)

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

Language

eng

PubMed ID

28645539

Citation

Kan, Chen, et al. "Gli1-labeled Adult Mesenchymal Stem/progenitor Cells and Hedgehog Signaling Contribute to Endochondral Heterotopic Ossification." Bone, vol. 109, 2018, pp. 71-79.
Kan C, Chen L, Hu Y, et al. Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification. Bone. 2018;109:71-79.
Kan, C., Chen, L., Hu, Y., Ding, N., Li, Y., McGuire, T. L., Lu, H., Kessler, J. A., & Kan, L. (2018). Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification. Bone, 109, 71-79. https://doi.org/10.1016/j.bone.2017.06.014
Kan C, et al. Gli1-labeled Adult Mesenchymal Stem/progenitor Cells and Hedgehog Signaling Contribute to Endochondral Heterotopic Ossification. Bone. 2018;109:71-79. PubMed PMID: 28645539.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gli1-labeled adult mesenchymal stem/progenitor cells and hedgehog signaling contribute to endochondral heterotopic ossification. AU - Kan,Chen, AU - Chen,Lijun, AU - Hu,Yangyang, AU - Ding,Na, AU - Li,Yuyun, AU - McGuire,Tammy L, AU - Lu,Haimei, AU - Kessler,John A, AU - Kan,Lixin, Y1 - 2017/06/21/ PY - 2017/03/02/received PY - 2017/06/16/revised PY - 2017/06/19/accepted PY - 2017/6/25/pubmed PY - 2018/12/12/medline PY - 2017/6/25/entrez KW - Adult mesenchymal stem/progenitor cells (MSC) KW - CD133 KW - Gli1 KW - Hedgehog (Hh) signaling KW - Heterotopic ossification (HO) KW - Lineage tracing SP - 71 EP - 79 JF - Bone JO - Bone VL - 109 N2 - Heterotopic ossification (HO), acquired or hereditary, endochondral or intramembranous, is the formation of true bone outside the normal skeleton. Since perivascular Gli1+ progenitors contribute to injury induced organ fibrosis, and CD133 is expressed by a variety of populations of adult stem cells, this study utilized Cre-lox based genetic lineage tracing to test the contribution to endochondral HO of adult stem/progenitor cells that expressed either Gli1 or CD133. We found that both lineages contributed broadly to different normal tissues with distinct patterns, but that only Gli1-creERT labeled stem/progenitor cells contributed to all stages of endochondral HO in a BMP dependent, injury induced, transgenic mouse model. Hedgehog (Hh) signaling was abnormal at endochondral HO lesion sites with increased signaling surrounding the lesion but diminished signaling within it. Thus, local dysregulation of Hh signaling participates in the pathophysiology of endochondral HO. However, unlike a previous report of intramembranous HO, systemic inhibition of Hh signaling was insufficient to prevent the initiation of the endochondral HO process or to treat the existing endochondral HO, suggesting that Hh participates in, but is not essential for endochondral HO in this model. This could potentially reflect the underlying difference between intramembranous and endochondral HO. Nevertheless, identification of this novel stem/precursor cell population as a HO-contributing cell population provides a potential drugable target. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/28645539/Gli1_labeled_adult_mesenchymal_stem/progenitor_cells_and_hedgehog_signaling_contribute_to_endochondral_heterotopic_ossification_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S8756-3282(17)30213-2 DB - PRIME DP - Unbound Medicine ER -