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Updated: Jul 21, 2025
Transplantation of Induced Pluripotent Stem Cell-derived Mesoangioblast-like Myogenic Progenitors in Mouse Models of Muscle Regeneration
Published on: January 20, 2014
Chemokine/ITGA4 Interaction Directs iPSC-Derived Myogenic Progenitor Migration to Injury Sites in Aging Muscle for
Muhammad Ashraf1, Srinivas M Tipparaju1, Joung Woul Kim1
1Department of Pharmaceutical Sciences, USF Health Taneja College of Pharmacy, University of South Florida, Tampa, FL 33612, USA.
Abstract:
The failure of muscle to repair after injury during aging may be a major contributor to muscle mass loss. We recently generated muscle progenitor cells (MPCs) from human-induced pluripotent stem-cell (iPSC) cell lines using small molecules, CHIR99021 and Givinostat (Givi-MPCs) sequentially. Here, we test whether the chemokines overexpressed in injured endothelial cells direct MPC migration to the site by binding to their receptor, ITGA4. ITGA4 was heavily expressed in Givi-MPCs. To study the effects on the mobilization of Givi-MPCs, ITGA4 was knocked down by an ITGA4 shRNA lentiviral vector. With and without ITGA4 knocked down, cell migration in vitro and cell mobilization in vivo using aged NOD scid gamma (NSG) mice and mdx/scid mice were analyzed. The migration of shITGA4-Givi-MPCs was significantly impaired, as shown in a wound-healing assay. The knockdown of ITGA4 impaired the migration of Givi-MPCs towards human aortic endothelial cells (HAECs), in which CX3CL1 and VCAM-1 were up-regulated by the treatment of TNF-α compared with scramble ones using a transwell system. MPCs expressing ITGA4 sensed chemokines secreted by endothelial cells at the injury site as a chemoattracting signal to migrate to the injured muscle. The mobilization of Givi-MPCs was mediated by the ligand-receptor interaction, which facilitated their engraftment for repairing the sarcopenic muscle with injury.
Insights
Muscle progenitor cells (MPCs) use ITGA4 to sense injury signals and migrate to repair aged muscle. This finding is crucial for understanding and treating age-related muscle mass loss.
Area of Science:
- Regenerative Medicine
- Cell Biology
- Aging Research
Background:
- Muscle mass loss during aging is linked to impaired muscle repair after injury.
- Muscle progenitor cells (MPCs) are essential for muscle regeneration.
- Human-induced pluripotent stem-cell-derived MPCs (Givi-MPCs) offer a potential therapeutic source.
Purpose of the Study:
- To investigate the role of integrin alpha 4 (ITGA4) in directing Givi-MPC migration to sites of muscle injury.
- To determine if chemokines from injured endothelial cells, via ITGA4, guide MPCs to the injury site.
Main Methods:
- Generated Givi-MPCs from human iPSCs.
- Knocked down ITGA4 expression in Givi-MPCs using shRNA lentiviral vectors.
- Assessed cell migration in vitro (wound-healing, transwell assays) and cell mobilization in vivo using aged mouse models (NSG, mdx/scid).
Main Results:
- ITGA4 was highly expressed in Givi-MPCs.
- Knockdown of ITGA4 significantly impaired Givi-MPC migration in vitro and in vivo.
- Impaired migration was observed towards TNF-α-treated human aortic endothelial cells (HAECs) expressing CX3CL1 and VCAM-1.
Conclusions:
- MPCs expressing ITGA4 utilize chemokines from injured endothelial cells as chemoattractant signals for migration to injured muscle.
- Ligand-receptor interactions involving ITGA4 mediate Givi-MPC mobilization and subsequent engraftment for sarcopenic muscle repair.
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