Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition
Abstract Injuries to skeletal muscle are among the most common injuries in civilian and military populations, accounting for nearly 60% of extremity injuries. The standard of care for severe extremity injury has been focused upon limb salvage procedures and the utilization of tissue grafts or orthot...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | npj Regenerative Medicine |
| Online Access: | https://doi.org/10.1038/s41536-024-00346-2 |
| _version_ | 1827329370216202240 |
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| author | J. G. Bartolacci M. N. Behun J. P. Warunek T. Li A. Sahu G. K. Dwyer A. Lucas J. Rong F. Ambrosio H. R. Turnquist S. F. Badylak |
| author_facet | J. G. Bartolacci M. N. Behun J. P. Warunek T. Li A. Sahu G. K. Dwyer A. Lucas J. Rong F. Ambrosio H. R. Turnquist S. F. Badylak |
| author_sort | J. G. Bartolacci |
| collection | DOAJ |
| description | Abstract Injuries to skeletal muscle are among the most common injuries in civilian and military populations, accounting for nearly 60% of extremity injuries. The standard of care for severe extremity injury has been focused upon limb salvage procedures and the utilization of tissue grafts or orthotics in conjunction with rehabilitation to avoid amputation. Nonetheless, many patients have persistent strength and functional deficits that permanently impact their quality of life. Preclinical and clinical studies have shown that partial restoration of functional skeletal muscle tissue following injury can be achieved by the implantation of a biologic scaffold composed of extracellular matrix (ECM). These favorable outcomes are mediated, at least in part, through local immunomodulation. The mechanisms underlying this immunomodulatory effect, however, are poorly understood. The present study investigates a potential mechanistic driver of the immunomodulatory effects; specifically, the effect of selected ECM components upon inflammation resolution and repair. Results show that the host response to skeletal muscle injury is profoundly altered and functional recovery decreased in il33 −/− mice compared to age- and sex-matched wildtype counterparts by 14 days post-injury. Results also show that IL-33, contained within matrix-bound nanovesicles (MBV), supports skeletal muscle regeneration by regulating local macrophage activation toward a pro-remodeling phenotype via canonical and non-canonical pathways to improve functional recovery from injury compared to untreated il33 −/− counterparts. Taken together, these data suggest that MBV and their associated IL-33 cargo represent a novel homeostatic signaling mechanism that contributes to skeletal muscle repair. |
| first_indexed | 2024-03-07T15:32:08Z |
| format | Article |
| id | doaj.art-dd0c23d5c408456b8f09870666fecc78 |
| institution | Directory Open Access Journal |
| issn | 2057-3995 |
| language | English |
| last_indexed | 2024-03-07T15:32:08Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Regenerative Medicine |
| spelling | doaj.art-dd0c23d5c408456b8f09870666fecc782024-03-05T16:22:18ZengNature Portfolionpj Regenerative Medicine2057-39952024-01-019111110.1038/s41536-024-00346-2Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transitionJ. G. Bartolacci0M. N. Behun1J. P. Warunek2T. Li3A. Sahu4G. K. Dwyer5A. Lucas6J. Rong7F. Ambrosio8H. R. Turnquist9S. F. Badylak10Department of Bioengineering, University of PittsburghDepartment of Bioengineering, University of PittsburghDepartments of Surgery and Immunology, University of Pittsburgh Medical CenterDepartments of Surgery and Immunology, University of Pittsburgh Medical CenterDepartment of Physical Medicine and Rehabilitation Sciences, University of PittsburghDepartments of Surgery and Immunology, University of Pittsburgh Medical CenterDepartments of Surgery and Immunology, University of Pittsburgh Medical CenterMcGowan Institute for Regenerative MedicineDepartment of Bioengineering, University of PittsburghDepartments of Surgery and Immunology, University of Pittsburgh Medical CenterDepartment of Bioengineering, University of PittsburghAbstract Injuries to skeletal muscle are among the most common injuries in civilian and military populations, accounting for nearly 60% of extremity injuries. The standard of care for severe extremity injury has been focused upon limb salvage procedures and the utilization of tissue grafts or orthotics in conjunction with rehabilitation to avoid amputation. Nonetheless, many patients have persistent strength and functional deficits that permanently impact their quality of life. Preclinical and clinical studies have shown that partial restoration of functional skeletal muscle tissue following injury can be achieved by the implantation of a biologic scaffold composed of extracellular matrix (ECM). These favorable outcomes are mediated, at least in part, through local immunomodulation. The mechanisms underlying this immunomodulatory effect, however, are poorly understood. The present study investigates a potential mechanistic driver of the immunomodulatory effects; specifically, the effect of selected ECM components upon inflammation resolution and repair. Results show that the host response to skeletal muscle injury is profoundly altered and functional recovery decreased in il33 −/− mice compared to age- and sex-matched wildtype counterparts by 14 days post-injury. Results also show that IL-33, contained within matrix-bound nanovesicles (MBV), supports skeletal muscle regeneration by regulating local macrophage activation toward a pro-remodeling phenotype via canonical and non-canonical pathways to improve functional recovery from injury compared to untreated il33 −/− counterparts. Taken together, these data suggest that MBV and their associated IL-33 cargo represent a novel homeostatic signaling mechanism that contributes to skeletal muscle repair.https://doi.org/10.1038/s41536-024-00346-2 |
| spellingShingle | J. G. Bartolacci M. N. Behun J. P. Warunek T. Li A. Sahu G. K. Dwyer A. Lucas J. Rong F. Ambrosio H. R. Turnquist S. F. Badylak Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition npj Regenerative Medicine |
| title | Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition |
| title_full | Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition |
| title_fullStr | Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition |
| title_full_unstemmed | Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition |
| title_short | Matrix-bound nanovesicle-associated IL-33 supports functional recovery after skeletal muscle injury by initiating a pro-regenerative macrophage phenotypic transition |
| title_sort | matrix bound nanovesicle associated il 33 supports functional recovery after skeletal muscle injury by initiating a pro regenerative macrophage phenotypic transition |
| url | https://doi.org/10.1038/s41536-024-00346-2 |
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