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Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

ABSTRACT: Heterotopic ossification (HO) occurs secondary to trauma, causing pain and functional limitations. Identification of the cells that contribute to HO is critical to the development of therapies. Given that innate immune cells and mesenchymal stem cells are known contributors to HO, we sought to define the contribution of these populations to HO and to identify what, if any, contribution circulating populations have to HO. A shared circulation was obtained using a parabiosis model, established between an enhanced green fluorescent protein-positive/luciferase+ donor and a same-strain nonreporter recipient mouse. The nonreporter mouse received Achilles tendon transection and dorsal burn injury to induce HO formation. Bioluminescence imaging and immunostaining were performed to define the circulatory contribution of immune and mesenchymal cell populations. Histologic analysis showed circulating cells present throughout each stage of the developing HO anlagen. Circulating cells were present at the injury site during the inflammatory phase and proliferative period, with diminished contribution in mature HO. Immunostaining demonstrated that most early circulatory cells were from the innate immune system; only a small population of mesenchymal cells were present in the HO. We demonstrate the time course of the participation of circulatory cells in trauma-induced HO and identify populations of circulating cells present in different stages of HO. These findings further elucidate the relative contribution of local and systemic cell populations to HO.

SUBMITTER: Loder SJ

PROVIDER: S-EPMC6222270 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

Loder Shawn J SJ Agarwal Shailesh S Chung Michael T MT Cholok David D Hwang Charles C Visser Noelle N Vasquez Kaetlin K Sorkin Michael M Habbouche Joe J Sung Hsiao H HH Peterson Joshua J Fireman David D Ranganathan Kavitha K Breuler Christopher C Priest Caitlin C Li John J Bai Xue X Li Shuli S Cederna Paul S PS Levi Benjamin B

The American journal of pathology 20180822 11

Heterotopic ossification (HO) occurs secondary to trauma, causing pain and functional limitations. Identification of the cells that contribute to HO is critical to the development of therapies. Given that innate immune cells and mesenchymal stem cells are known contributors to HO, we sought to define the contribution of these populations to HO and to identify what, if any, contribution circulating populations have to HO. A shared circulation was obtained using a parabiosis model, established bet ...[more]

PMID: 30142335

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Project description:BackgroundTraumatic heterotopic ossification (THO) is a devastating sequela following traumatic injuries and orthopedic surgeries. To date, the exact molecular mechanism of THO formation is still unclear, which hinders the development of effective treatments. The process of THO formation is believed to recapitulate a series of spatiotemporal cellular and signaling events that occur during skeletal development. The Notch signaling pathway is a critical genetic regulator in embryological bone development and fracture healing. However, few data are available concerning whether Notch signaling regulates THO development and maturation.MethodsWe firstly detected the expressions of Notch target genes in both mouse and human THO samples with quantitative RT-PCR and immunohistochemistry (IHC). Then, tissue-resident mesenchymal progenitor cells (TMPCs) were isolated, and the abilities of the proliferation and osteogenic and chondrogenic differentiation of TMPCs were examined under the intervention of the gamma-secretase inhibitor-DAPT at different time points. Finally, DAPT was also administrated in THO mice by burn and Achilles tenotomy injury, and ectopic cartilage and bone formation were monitored by histology and micro-CT.ResultsSeveral Notch target genes were upregulated in both mouse and human THO tissues. Sustained Notch signaling inhibition by DAPT reduced proliferation, osteogenic and chondrogenic differentiation of TMPCs in a time-dependent manner. Moreover, DAPT administration within 3 weeks could inhibit ectopic cartilage and bone formation in a mouse THO model without affecting the total body bone mass.ConclusionsThe Notch signaling serves as an important therapeutic target during THO formation. And sustained gamma-secretase inhibition by DAPT has great potential in repressing chondrogenic and osteogenic differentiation of TMPCs, as well as inhibited ectopic cartilage and bone formation in vivo.The translational potential of this articleSustained Notch inhibition via systemic DAPT (or other similar gamma-secretase inhibitors) administration has promising clinical utility for inhibiting THO formation, providing new insight into THO prophylaxis and treatment.

Project description:BackgroundTraumatic heterotopic ossification (HO) is an intractable sequela incited by inflammatory insult. To date, the exact molecular mechanisms of traumatic HO formation remain unclear. Recent studies have indicated that circular RNAs (circRNAs) participate in various human skeletal diseases. Although the formation of HO recapitulates many programs during bone development and remodeling, few data are available concerning whether circRNAs could participate in this pathological osteogenesis.MethodsTo investigate the differentially expressed circRNAs (DE-circRNAs) in HO formation, microarray assay was performed to analyze the circRNA expression profile in four pairs of mice HO tissues and normal tissues. Then, qRT-PCR was applied to verify the microarray data. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses showed the biological functions of the differentially expressed circRNAs target genes. Cytoscape software was used to construct the circRNA-miRNA-mRNA network for circRNAs with different expression levels as well as the target genes.ResultsWe demonstrated that 491 circRNAs were significantly differentially expressed in mouse HO tissues by a fold-change ≥ 2 and p-value ≤ 0.05. Among them, the expressions of 168 circRNAs were increased, while 323 were decreased. The expression levels of 10 selected circRNAs were verified successfully by qRT-PCR. GO analysis exhibited that these DE-circRNAs participated in a series of cellular processes. KEGG pathway analysis revealed that multiple upregulated and downregulated pathways were closely related to the DE-circRNAs in HO mice. The circRNA-miRNA-mRNA networks demonstrated that DE-circRNAs may be involved in the pathological osteogenesis of HO through the circRNA-targeted miRNA-mRNA axis.ConclusionOur study first demonstrated the expression profiles and predicted the potential functions of DE-circRNAs in mice traumatic HO, which may shed new light on the elucidation of mechanisms as well as provide novel potential peripheral biological diagnostic markers and therapeutic targets for traumatic HO.

Dataset Information

Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

Publications

Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

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