Academic Appointments

Honors & Awards

  • K99 Pathway to Independence, NIA/NIH
  • T32 Training Grant, NIA/NIH/Buck Institute

Research & Scholarship

Current Research and Scholarly Interests

Stem cell fate determination and microenvironment dynamics


All Publications

  • Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nature communications Du, H., Shih, C. H., Wosczyna, M. N., Mueller, A. A., Cho, J., Aggarwal, A., Rando, T. A., Feldman, B. J. 2017; 8 (1): 669


    Coordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration. The muscle stem cell niche is central for regulating the activation state of satellite cells, but the specific extracellular signals that coordinate this regulation are poorly understood. Here we show that macrophages at sites of muscle injury induce activation of satellite cells via expression of Adamts1. Overexpression of Adamts1 in macrophages in vivo is sufficient to increase satellite cell activation and improve muscle regeneration in young mice. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite cell activation. These results identify Adamts1 as a potent extracellular regulator of satellite cell activation and have significant implications for understanding the regulation of satellite cell activity and regeneration after muscle injury.Satellite cells are crucial for growth and regeneration of skeletal muscle. Here the authors show that in response to muscle injury, macrophages secrete Adamts1, which induces satellite cell activation by modulating Notch1 signaling.

    View details for DOI 10.1038/s41467-017-00522-7

    View details for PubMedID 28939843

  • Multipotent progenitors resident in the skeletal muscle interstitium exhibit robust BMP-dependent osteogenic activity and mediate heterotopic ossification JOURNAL OF BONE AND MINERAL RESEARCH Wosczyna, M. N., Biswas, A. A., Cogswell, C. A., Goldhamer, D. J. 2012; 27 (5): 1004-1017


    Heterotopic ossification is a debilitating condition that can result from traumatic injury, surgery, or genetic disease. We investigated the cellular origins of heterotopic skeletogenesis in the mouse using lineage tracing and bioassays of heterotopic ossification based on intramuscular transplantation. We identified, characterized, and purified a tissue-resident stem/progenitor cell population that exhibits robust osteogenic potential and represents a major cell-of-origin for heterotopic ossification. These progenitors reside in the interstitium of skeletal muscle and other tissues, and are distinct from the endothelium, which does not exhibit osteogenic activity in response to bone morphogenetic protein 2 (BMP2) stimulation. Intramuscular transplantation, together with clonal analysis in culture, revealed that these progenitors are multipotent, exhibiting the capacity for both BMP-dependent skeletogenic differentiation and spontaneous adipogenic differentiation. Identifying the cells-of-origin responsible for heterotopic ossification provides a potential therapeutic target to treat, mitigate, or prevent this disabling condition.

    View details for DOI 10.1002/jbmr.1562

    View details for Web of Science ID 000302939400006

    View details for PubMedID 22307978

  • Identification of progenitor cells that contribute to heterotopic skeletogenesis. journal of bone and joint surgery. American volume Lounev, V. Y., Ramachandran, R., Wosczyna, M. N., Yamamoto, M., Maidment, A. D., Shore, E. M., Glaser, D. L., Goldhamer, D. J., Kaplan, F. S. 2009; 91 (3): 652-663


    Individuals who have fibrodysplasia ossificans progressiva develop an ectopic skeleton because of genetic dysregulation of bone morphogenetic protein (BMP) signaling in the presence of inflammatory triggers. The identity of progenitor cells that contribute to various stages of BMP-induced heterotopic ossification relevant to fibrodysplasia ossificans progressiva and related disorders is unknown. An understanding of the cellular basis of heterotopic ossification will aid in the development of targeted, cell-specific therapies for the treatment and prevention of heterotopic ossification.We used Cre/loxP lineage tracing methods in the mouse to identify cell lineages that contribute to all stages of heterotopic ossification. Specific cell populations were permanently labeled by crossing lineage-specific Cre mice with the Cre-dependent reporter mice R26R and R26R-EYFP. Two mouse models were used to induce heterotopic ossification: (1) intramuscular injection of BMP2/Matrigel and (2) cardiotoxin-induced skeletal muscle injury in transgenic mice that misexpress BMP4 at the neuromuscular junction. The contribution of labeled cells to fibroproliferative lesions, cartilage, and bone was evaluated histologically by light and fluorescence microscopy. The cell types evaluated as possible progenitors included skeletal muscle stem cells (MyoD-Cre), endothelium and endothelial precursors (Tie2-Cre), and vascular smooth muscle (Smooth Muscle Myosin Heavy Chain-Cre [SMMHC-Cre]).Vascular smooth muscle cells did not contribute to any stage of heterotopic ossification in either mouse model. Despite the osteogenic response of cultured skeletal myoblasts to BMPs, skeletal muscle precursors in vivo contributed minimally to heterotopic ossification (<5%), and this contribution was not increased by cardiotoxin injection, which induces muscle regeneration and mobilizes muscle stem cells. In contrast, cells that expressed the vascular endothelial marker Tie2/Tek at some time in their developmental history contributed robustly to the fibroproliferative, chondrogenic, and osteogenic stages of the evolving heterotopic endochondral anlagen. Importantly, endothelial markers were expressed by cells at all stages of heterotopic ossification. Finally, muscle injury and associated inflammation were sufficient to trigger fibrodysplasia ossificans progressiva-like heterotopic ossification in a setting of chronically stimulated BMP activity.Tie2-expressing progenitor cells, which are endothelial precursors, respond to an inflammatory trigger, differentiate through an endochondral pathway, contribute to every stage of the heterotopic endochondral anlagen, and form heterotopic bone in response to overactive BMP signaling in animal models of fibrodysplasia ossificans progressiva. Thus, the ectopic skeleton is not only supplied by a rich vasculature, but appears to be constructed in part by cells of vascular origin. Further, these data strongly suggest that dysregulation of the BMP signaling pathway and an inflammatory microenvironment are both required for the formation of fibrodysplasia ossificans progressiva-like lesions.

    View details for DOI 10.2106/JBJS.H.01177

    View details for PubMedID 19255227

  • A Multifunctional Reporter Mouse Line for Cre- and FLP-Dependent Lineage Analysis GENESIS Yamamoto, M., Shook, N. A., Kanisicak, O., Yamamoto, S., Wosczyna, M. N., Camp, J. R., Goldhamer, D. J. 2009; 47 (2): 107-114


    The Cre/lox and FLP/FRT recombination systems have been used extensively for both conditional knockout and cell lineage analysis in mice. Here we report a new multifunctional Cre/FLP dual reporter allele (R26(NZG)) that exhibits strong and apparently ubiquitous marker expression in embryos and adults. The reporter construct, which is driven by the CAG promoter, was knocked into the ROSA26 locus providing an open chromatin domain for consistent expression and avoiding site-of-integration effects often observed with transgenic reporters. R26(NZG) directs Cre-dependent nuclear-localized beta-galactosidase (beta-gal) expression, and can be converted into a Cre-dependent EGFP reporter (R26(NG)) by germline excision of the FRT-flanked nlslacZ cassette. Alternatively, germline excision of the floxed PGKNEO cassette in R26(NZG) generates an FLP-dependent EGFP reporter (R26(ZG)) that expresses beta-gal in FLP-nonexpressing cells. Finally, by the simultaneous use of both Cre and FLP deleters, R26(NZG) allows lineage relationships to be interrogated with greater refinement than is possible with single recombinase reporter systems.

    View details for DOI 10.1002/dvg.20474

    View details for Web of Science ID 000263887700006

    View details for PubMedID 19165827