Distinct human skeletal muscle-derived CD90 progenitor subsets for myo-fibro-adipogenic disease modeling and treatment in multiplexed conditions
Chronic muscle injuries, such as massive rotator cuff tears, are associated with progressive muscle wasting, fibrotic scarring, and intramuscular fat accumulation. While progenitor cell subsets are usually studied in culture conditions that drive either myogenic, fibrogenic, or adipogenic differenti...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1173794/full |
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| author | Angela Li Madhavan Anbuchelvan Amir Fathi Maya Abu-Zahra Denis Evseenko Denis Evseenko Frank A. Petrigliano Ayelet Dar |
| author_facet | Angela Li Madhavan Anbuchelvan Amir Fathi Maya Abu-Zahra Denis Evseenko Denis Evseenko Frank A. Petrigliano Ayelet Dar |
| author_sort | Angela Li |
| collection | DOAJ |
| description | Chronic muscle injuries, such as massive rotator cuff tears, are associated with progressive muscle wasting, fibrotic scarring, and intramuscular fat accumulation. While progenitor cell subsets are usually studied in culture conditions that drive either myogenic, fibrogenic, or adipogenic differentiation, it is still unknown how combined myo-fibro-adipogenic signals, which are expected to occur in vivo, modulate progenitor differentiation. We therefore evaluated the differentiation potential of retrospectively generated subsets of primary human muscle mesenchymal progenitors in multiplexed conditions in the presence or absence of 423F drug, a modulator of gp130 signaling. We identified a novel CD90+CD56− non-adipogenic progenitor subset that maintained a lack of adipogenic potential in single and multiplexed myo-fibro-adipogenic culture conditions. CD90−CD56− demarcated fibro-adipogenic progenitors (FAP) and CD56+CD90+ progenitors were typified as myogenic. These human muscle subsets exhibited varying degrees of intrinsically regulated differentiation in single and mixed induction cultures. Modulation of gp130 signaling via 423F drug mediated muscle progenitor differentiation in a dose-, induction-, and cell subset-dependent manner and markedly decreased fibro-adipogenesis of CD90−CD56− FAP. Conversely, 423F promoted myogenesis of CD56+CD90+ myogenic subset, indicated by increased myotube diameter and number of nuclei per myotube. 423F treatment eliminated FAP-derived mature adipocytes from mixed adipocytes-FAP cultures but did not modify the growth of non-differentiated FAP in these cultures. Collectively, these data demonstrate that capability of myogenic, fibrogenic, or adipogenic differentiation is largely dependent on the intrinsic features of cultured subsets, and that the degree of lineage differentiation varies when signals are multiplexed. Moreover, our tests performed in primary human muscle cultures reveal and confirm the potential triple-therapeutic effects of 423F drug which simultaneously attenuates degenerative fibrosis, fat accumulation and promotes myo-regeneration. |
| first_indexed | 2024-04-09T17:31:31Z |
| format | Article |
| id | doaj.art-7d5dd77d2da74d78bd388082b543cf9c |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-09T17:31:31Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-7d5dd77d2da74d78bd388082b543cf9c2023-04-18T04:59:54ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2023-04-011110.3389/fcell.2023.11737941173794Distinct human skeletal muscle-derived CD90 progenitor subsets for myo-fibro-adipogenic disease modeling and treatment in multiplexed conditionsAngela Li0Madhavan Anbuchelvan1Amir Fathi2Maya Abu-Zahra3Denis Evseenko4Denis Evseenko5Frank A. Petrigliano6Ayelet Dar7Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Stem Cell Research and Regenerative Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesDepartment of Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United StatesChronic muscle injuries, such as massive rotator cuff tears, are associated with progressive muscle wasting, fibrotic scarring, and intramuscular fat accumulation. While progenitor cell subsets are usually studied in culture conditions that drive either myogenic, fibrogenic, or adipogenic differentiation, it is still unknown how combined myo-fibro-adipogenic signals, which are expected to occur in vivo, modulate progenitor differentiation. We therefore evaluated the differentiation potential of retrospectively generated subsets of primary human muscle mesenchymal progenitors in multiplexed conditions in the presence or absence of 423F drug, a modulator of gp130 signaling. We identified a novel CD90+CD56− non-adipogenic progenitor subset that maintained a lack of adipogenic potential in single and multiplexed myo-fibro-adipogenic culture conditions. CD90−CD56− demarcated fibro-adipogenic progenitors (FAP) and CD56+CD90+ progenitors were typified as myogenic. These human muscle subsets exhibited varying degrees of intrinsically regulated differentiation in single and mixed induction cultures. Modulation of gp130 signaling via 423F drug mediated muscle progenitor differentiation in a dose-, induction-, and cell subset-dependent manner and markedly decreased fibro-adipogenesis of CD90−CD56− FAP. Conversely, 423F promoted myogenesis of CD56+CD90+ myogenic subset, indicated by increased myotube diameter and number of nuclei per myotube. 423F treatment eliminated FAP-derived mature adipocytes from mixed adipocytes-FAP cultures but did not modify the growth of non-differentiated FAP in these cultures. Collectively, these data demonstrate that capability of myogenic, fibrogenic, or adipogenic differentiation is largely dependent on the intrinsic features of cultured subsets, and that the degree of lineage differentiation varies when signals are multiplexed. Moreover, our tests performed in primary human muscle cultures reveal and confirm the potential triple-therapeutic effects of 423F drug which simultaneously attenuates degenerative fibrosis, fat accumulation and promotes myo-regeneration.https://www.frontiersin.org/articles/10.3389/fcell.2023.1173794/fullhuman muscle mesenchymal subsetsskeletal muscle differentiationCD90gp130 signalingmyo-fibro-adipogenesisin vitro drug screening |
| spellingShingle | Angela Li Madhavan Anbuchelvan Amir Fathi Maya Abu-Zahra Denis Evseenko Denis Evseenko Frank A. Petrigliano Ayelet Dar Distinct human skeletal muscle-derived CD90 progenitor subsets for myo-fibro-adipogenic disease modeling and treatment in multiplexed conditions Frontiers in Cell and Developmental Biology human muscle mesenchymal subsets skeletal muscle differentiation CD90 gp130 signaling myo-fibro-adipogenesis in vitro drug screening |
| title | Distinct human skeletal muscle-derived CD90 progenitor subsets for myo-fibro-adipogenic disease modeling and treatment in multiplexed conditions |
| title_full | Distinct human skeletal muscle-derived CD90 progenitor subsets for myo-fibro-adipogenic disease modeling and treatment in multiplexed conditions |
| title_fullStr | Distinct human skeletal muscle-derived CD90 progenitor subsets for myo-fibro-adipogenic disease modeling and treatment in multiplexed conditions |
| title_full_unstemmed | Distinct human skeletal muscle-derived CD90 progenitor subsets for myo-fibro-adipogenic disease modeling and treatment in multiplexed conditions |
| title_short | Distinct human skeletal muscle-derived CD90 progenitor subsets for myo-fibro-adipogenic disease modeling and treatment in multiplexed conditions |
| title_sort | distinct human skeletal muscle derived cd90 progenitor subsets for myo fibro adipogenic disease modeling and treatment in multiplexed conditions |
| topic | human muscle mesenchymal subsets skeletal muscle differentiation CD90 gp130 signaling myo-fibro-adipogenesis in vitro drug screening |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1173794/full |
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