Mesodermal iPSC-derived progenitor cells functionally regenerate cardiac and skeletal muscle

Area of Science:

• Regenerative Medicine
• Stem Cell Biology
• Muscle Biology

Background:

• Muscular dystrophies (MDs) affect both cardiac and skeletal muscles, necessitating therapies that regenerate both striated muscle types.
• Current induced pluripotent stem cell (iPSC) differentiation protocols target either cardiac or skeletal muscle, lacking simultaneous dual-targeting strategies.
• Epigenetic alterations in tissues suggest source-related lineage biases can enhance iPSC-driven multilineage differentiation.

Purpose of the Study:

• To investigate the potential of mesodermal iPSC-derived progenitors (MiPs) for simultaneous regeneration of cardiac and skeletal muscles.
• To determine if differential myogenic propensity influences iPSC commitment to striated muscle lineages.
• To evaluate MiPs as a therapeutic strategy for muscular dystrophies.

Main Methods:

• Isolated mesodermal iPSC-derived progenitors (MiPs) from isogenic iPSCs.
• Assessed differential myogenic propensity and its effect on iPSC commitment and tissue chimerism.
• Injected MiPs into dystrophic mouse models (murine and canine) and evaluated engraftment, muscle repair, and functional recovery.
• Tested human MiPs for dual differentiation capacity.

Main Results:

• Differential myogenic propensity enhanced MiP-derived tissue chimerism in skeletal muscle.
• MiPs engrafted and repaired both skeletal and cardiac muscle in dystrophic mice, reducing functional deficits.
• Canine MiPs from corrected dystrophic dogs and human MiPs demonstrated similar dual differentiation capacity.

Conclusions:

• Mesodermal iPSC-derived progenitors (MiPs) possess the capacity for simultaneous cardiac and skeletal muscle regeneration.
• MiPs represent a promising candidate for combined therapeutic strategies targeting muscular dystrophies.
• Further exploration of MiPs is warranted for treating conditions affecting both cardiac and skeletal muscles.