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A Yonsei University research team has developed a new cell reprogramming technique that could offer an alternative treatment option for patients with ischemic cardiovascular disease who are ineligible for surgery or fail to respond to current interventional procedures.
A Yonsei University research team, led by Professor Yoon Young-sup (left) and researcher Jung Cho-lomi, developed a novel cell reprogramming method for ischemic cardiovascular disease treatment. (Credit: Severance Hospital)
A Yonsei University research team, led by Professor Yoon Young-sup (left) and researcher Jung Cho-lomi, developed a novel cell reprogramming method for ischemic cardiovascular disease treatment. (Credit: Severance Hospital)
Ischemic cardiovascular disease, identified by the World Health Organization (WHO) as one of the top 10 causes of death worldwide, is a major global health concern due to its high mortality rate. While current treatment options include pharmacotherapy, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG), patients who fail to respond to these interventions or are inoperable are often left without viable alternatives.
In recent years, stem cell-based therapies aimed at promoting neovascularization have gained attention. However, these approaches face limitations such as low differentiation efficiency, potential tumorigenicity, and high production costs. To overcome these challenges, researchers have turned to direct reprogramming, a method that induces lineage conversion by overexpressing key transcription factors in somatic cells.
The Yonsei research team, led by Professor Yoon Young-sup of the Severance Biomedical Science Institute and researcher Jung Cho-lomi of the Department of Internal Medicine at Yonsei University College of Medicine, focused on reprogramming human dermal fibroblasts into vascular smooth muscle cells—key components of stable blood vessels.
Unlike previously developed methods that reprogrammed cells into endothelial cells, this new approach offers the advantage of forming thicker and more structurally stable vasculature.
To achieve this, the researchers used myocardin, a master transcription factor for SMCs, in combination with all-trans retinoic acid, a metabolite of vitamin A. This combination successfully induced the direct transdifferentiation of fibroblasts into rSMCs.
These rSMCs showed significantly increased expression of SMC-specific genes and proteins. Immunostaining confirmed the presence of characteristic cytoskeletal structures, and flow cytometry analysis revealed high expression levels of ACTA2 and MYH11—key markers of smooth muscle cells—at 57.2±11.9 percent and 48.0±7.7 percent, respectively.
The cells also displayed robust contractility in response to carbachol, a cholinergic agonist, confirming their functional characteristics. Further RNA-sequencing analyses showed suppression of fibroblast-specific genes and enhanced expression of contractile and SMC-specific genes.
To evaluate the therapeutic efficacy of rSMCs, the team used a mouse model of hindlimb ischemia. Upon direct injection of rSMCs, the treated group exhibited improved blood perfusion and vessel formation compared to control groups, including fibroblast-only and no-cell groups.
Notably, the rSMCs integrated into the vascular wall, forming new layers and functioning as previously unrecognized perivascular cells. These cells contributed to the structure of capillaries, arterioles, and small arteries, suggesting a novel role in microvascular reconstruction.
“This study demonstrates the viability and functionality of transplanted smooth muscle cells in vivo and opens up new therapeutic possibilities for patients with ischemic cardiovascular diseases,” Professor Yoon said. “Follow-up studies are expected to yield tangible outcomes in broader medical applications such as cell therapy products, vascular tissue engineering, and drug development.”
Their findings were published in Circulation, the official journal of theAmerican Heart Association.
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Lee Han-soo corea022@docdocdoc.co.kr
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