Publications by authors named "Kaetlin Vasquez"

8 Publications

  • Page 1 of 1

Novel Lineage-Tracing System to Identify Site-Specific Ectopic Bone Precursor Cells.

Stem Cell Reports 2021 Mar 18;16(3):626-640. Epub 2021 Feb 18.

Center for Organogenesis and Trauma, Department of Surgery, University of Texas Southwestern, 6000 Harry Hines Boulevard, Dallas, TX 75235, USA. Electronic address:

Heterotopic ossification (HO) is a form of pathological cell-fate change of mesenchymal stem/precursor cells (MSCs) that occurs following traumatic injury, limiting range of motion in extremities and causing pain. MSCs have been shown to differentiate to form bone; however, their lineage and aberrant processes after trauma are not well understood. Utilizing a well-established mouse HO model and inducible lineage-tracing mouse (Hoxa11-CreER;ROSA26-LSL-TdTomato), we found that Hoxa11-lineage cells represent HO progenitors specifically in the zeugopod. Bioinformatic single-cell transcriptomic and epigenomic analyses showed Hoxa11-lineage cells are regionally restricted mesenchymal cells that, after injury, gain the potential to undergo differentiation toward chondrocytes, osteoblasts, and adipocytes. This study identifies Hoxa11-lineage cells as zeugopod-specific ectopic bone progenitors and elucidates the fate specification and multipotency that mesenchymal cells acquire after injury. Furthermore, this highlights homeobox patterning genes as useful tools to trace region-specific progenitors and enable location-specific gene deletion.
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http://dx.doi.org/10.1016/j.stemcr.2021.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940250PMC
March 2021

Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification.

Bone Res 2019 Dec 10;7(1):36. Epub 2019 Dec 10.

Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is a debilitating condition characterized by the pathologic formation of ectopic bone. HO occurs commonly following orthopedic surgeries, burns, and neurologic injuries. While surgical excision may provide palliation, the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone. Based on these clinical observations, we set out to examine the role of vascular signaling in HO. Vascular endothelial growth factor A (VEGFA) has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis. Our findings, using a validated mouse model of HO, demonstrate that HO lesions are highly vascular, and that VEGFA is critical to ectopic bone formation, despite lacking a contribution of endothelial cells within the developing anlagen.
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http://dx.doi.org/10.1038/s41413-019-0075-6DOI Listing
December 2019

Tuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis.

J Immunol 2020 04 11;204(8):2203-2215. Epub 2020 Mar 11.

Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

Myeloid cells are critical to the development of fibrosis following muscle injury; however, the mechanism of their role in fibrosis formation remains unclear. In this study, we demonstrate that myeloid cell-derived TGF-β1 signaling is increased in a profibrotic ischemia reperfusion and cardiotoxin muscle injury model. We found that myeloid-specific deletion of abrogates the fibrotic response in this injury model and reduces fibro/adipogenic progenitor cell proliferation while simultaneously enhancing muscle regeneration, which is abrogated by adaptive transfer of normal macrophages. Similarly, a murine TGFBRII-Fc ligand trap administered after injury significantly reduced muscle fibrosis and improved muscle regeneration. This study ultimately demonstrates that infiltrating myeloid cell TGF-β1 is responsible for the development of traumatic muscle fibrosis, and its blockade offers a promising therapeutic target for preventing muscle fibrosis after ischemic injury.
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http://dx.doi.org/10.4049/jimmunol.1900814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080967PMC
April 2020

Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing.

Nat Commun 2020 02 5;11(1):722. Epub 2020 Feb 5.

Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
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http://dx.doi.org/10.1038/s41467-019-14172-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002453PMC
February 2020

Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification.

Bone Res 2019 10;7:36. Epub 2019 Dec 10.

1Department of Surgery, University of Michigan, Ann Arbor, MI 48109 USA.

Heterotopic ossification (HO) is a debilitating condition characterized by the pathologic formation of ectopic bone. HO occurs commonly following orthopedic surgeries, burns, and neurologic injuries. While surgical excision may provide palliation, the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone. Based on these clinical observations, we set out to examine the role of vascular signaling in HO. Vascular endothelial growth factor A (VEGFA) has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis. Our findings, using a validated mouse model of HO, demonstrate that HO lesions are highly vascular, and that VEGFA is critical to ectopic bone formation, despite lacking a contribution of endothelial cells within the developing anlagen.
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http://dx.doi.org/10.1038/s41413-019-0075-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904752PMC
December 2019

Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease.

J Orthop Res 2020 04 25;38(4):708-718. Epub 2019 Nov 25.

Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, New York.

In this review, we highlight themes from a recent workshop focused on "Plasticity of Cell Fate in Musculoskeletal Tissues" held at the Orthopaedic Research Society's 2019 annual meeting. Experts in the field provided examples of mesenchymal cell plasticity during normal musculoskeletal development, regeneration, and disease. A thorough understanding of the biology underpinning mesenchymal cell plasticity may offer a roadmap for promoting regeneration while attenuating pathologic differentiation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:708-718, 2020.
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http://dx.doi.org/10.1002/jor.24523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213644PMC
April 2020

Investigation into Possible Association of Oxandrolone and Heterotopic Ossification Following Burn Injury.

J Burn Care Res 2019 06;40(4):398-405

Massachusetts General Hospital, Boston.

Oxandrolone, a testosterone analog, is used to counteract the catabolic effects of burn injury. Recent animal studies suggest a possible hormonal association with heterotopic ossification (HO) development postburn. This work examines oxandrolone administration and HO development by exploring historical clinical data bridging the introduction of oxandrolone into clinical practice. Additionally, we examine associations between oxandrolone administration and HO in a standardized mouse model of burn/trauma-related HO. Acutely burned adults admitted between 2000 and 2014, survived through discharge, and had a HO risk factor of 7 or higher were selected for analysis from a single burn center. Oxandrolone administration, clinical and demographic data, and elbow HO were recorded and were analyzed with logistic regression. Associations of oxandrolone with HO were examined in a mouse model. Mice were administered oxandrolone or vehicle control following burn/tenotomy to examine any potential effect of oxandrolone on HO and were analyzed by Student's t test. Subjects who received oxandrolone had a higher incidence of elbow HO than those that did not receive oxandrolone. However, when controlling for oxandrolone administration, oxandrolone duration, postburn day oxandrolone initiation, HO risk score category, age, sex, race, burn size, and year of injury, there was no significant difference between rates of elbow HO between the two populations. In agreement with the review, in the mouse model, while there was a trend toward the oxandrolone group developing a greater volume of HO, this did not reach statistical significance.
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http://dx.doi.org/10.1093/jbcr/irz063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587410PMC
June 2019

Characterizing the Circulating Cell Populations in Traumatic Heterotopic Ossification.

Am J Pathol 2018 11 22;188(11):2464-2473. Epub 2018 Aug 22.

Burn/Wound and Regenerative Medicine Laboratory, Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ajpath.2018.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222270PMC
November 2018