Breakthrough in Heart Attack Recovery: Follistatin-Driven Cardiomyocyte Proliferation Offers New Hope
Heart attacks remain a leading cause of death and disability worldwide, with a grim prognosis for many patients. Half of those diagnosed with heart failure succumb within five years. The damage inflicted by a heart attack – the death of vital heart muscle cells (cardiomyocytes) and their replacement with non-contractile scar tissue – leads to a cascade of debilitating consequences: weakened heart function, enlargement, arrhythmias, and ultimately, end-stage heart failure. Though, a groundbreaking study from the university of Alabama at Birmingham (UAB) offers a beacon of hope, revealing a novel pathway to stimulate the heart’s own regenerative capacity. This research, building on previous successes, identifies follistatin as a key inducer of cardiomyocyte proliferation, potentially revolutionizing treatment for heart attack survivors.
The Challenge of Heart Muscle regeneration
For decades, the prevailing understanding was that adult mammalian hearts possessed limited regenerative ability. Unlike some tissues, cardiomyocytes were considered largely incapable of dividing and replicating to repair damage. This lack of natural repair mechanisms has driven the search for innovative therapies to replace lost muscle tissue or, ideally, to stimulate the heart to heal itself. Previous research from the Zhang lab at UAB demonstrated promising results using heart muscle cells engineered to overexpress cyclin D2, a protein crucial for cell division. Though, these studies were limited by the use of immunocompromised mice, hindering direct translation to human applications.
A Novel Approach: Harnessing the Power of hiPSC-Cardiomyocytes and follistatin
The current UAB study overcomes this hurdle by utilizing hypoimmunogenic, cyclin D2-overexpressing human induced pluripotent stem cell-derived cardiomyocytes (KO/OEhiPSC-cardiomyocytes) in a large-animal model – pigs – more closely mirroring human physiology. Researchers observed a surprising phenomenon: instead of the injected cells directly replacing damaged tissue, they triggered a significant increase in the proliferation of existing heart muscle cells.
This wasn’t simply a minor uptick in activity. The endogenous cardiomyocytes – those already present in the heart - began to divide, exhibiting elevated levels of cellular proliferation markers and genes associated with DNA replication. Further examination revealed upregulation of three critical signaling pathways known to regulate cell growth: the Mitogen-Activated Protein Kinase (MAPK) pathway, the HIPPO/YAP pathway, and the Transforming Growth factor Β (TGF-β) pathway.
Crucially, the team ruled out direct signaling from the surface receptors of the endogenous cardiomyocytes, suggesting the stimulus originated outside the cells themselves. This led them to focus on the secreted proteins produced by the KO/OEhiPSC-cardiomyocytes.
Follistatin: The Key to Unlocking Cardiac Regeneration
Through detailed cytokine array analysis, researchers pinpointed follistatin, an autocrine glycoprotein, as the prime candidate. KO/OEhiPSC-cardiomyocytes were found to secrete high levels of follistatin. Subsequent experiments confirmed its potent regenerative effect:
In vitro: Human cardiomyocytes treated with follistatin exhibited a 30% increase in cell number.
In vivo: In a mouse model of heart attack (myocardial infarction), injected follistatin induced proliferation of adult mouse cardiomyocytes, demonstrating its efficacy in a living organism.
Mechanism of Action: Further research confirmed that follistatin specifically targets the HIPPO/YAP signaling pathway, a key regulator of organ size and cell growth, to promote cardiomyocyte proliferation.
“To our knowledge, this is the first report demonstrating that follistatin promotes the proliferation of hiPSC-cardiomyocytes and cardiomyocytes from adult mammalian hearts,” stated Dr. Zhang, highlighting the novelty of this finding. While the precise mechanisms by which follistatin activates cardiomyocyte proliferation remain under investigation,the implications are profound.
Why This Matters: A Paradigm Shift in heart Attack treatment
This research represents a significant leap forward in cardiovascular medicine. Instead of focusing solely on replacing damaged tissue, the UAB team has identified a way to awaken the heart’s inherent regenerative potential. This approach offers several advantages:
Reduced Reliance on Cell Transplantation: Stimulating endogenous repair minimizes the need for extensive cell transplantation procedures.
Enhanced Therapeutic Efficacy: Leveraging the heart’s own repair mechanisms may lead to more robust and long-lasting recovery.
Potential for Clinical Translation: The use of a large-animal model and hypoimmunogenic cells increases the likelihood of successful translation to human clinical trials.
The study builds upon the team’s 2021 work with cyclin D2 overexpression, offering a potentially more refined and effective therapeutic strategy. The identification of
