Nam Yena, Song Yoonji, Seo Seung Ju, Ko Ga Ryang, Lee Seung Hyun, Cha Eunju, Kwak Su Min, Kim Sumin, Shin Mikyung, Jin Yoonhee, Lee Jung Seung
Department of Physiology Graduate School of Medical Science Brain Korea 21 Project Yonsei University College of Medicine Seoul Republic of Korea.
Department of Biomedical Engineering Sungkyunkwan University (SKKU) Suwon Republic of Korea.
MedComm (2020). 2024 Nov 28;5(12):e70005. doi: 10.1002/mco2.70005. eCollection 2024 Dec.
Heart degenerative diseases pose a significant challenge due to the limited ability of native heart to restore lost cardiomyocytes. Direct cellular reprogramming technology, particularly the use of small molecules, has emerged as a promising solution to prepare functional cardiomyocyte through faster and safer processes without genetic modification. However, current methods of direct reprogramming often exhibit low conversion efficiencies and immature characteristics of the generated cardiomyocytes, limiting their use in regenerative medicine. This study proposes the use of mitochondrial delivery to metabolically reprogram chemically induced cardiomyocyte-like cells (CiCMs), fostering enhanced maturity and functionality. Our findings show that mitochondria sourced from high-energy-demand organs (liver, brain, and heart) can enhance structural maturation and metabolic functions. Notably, heart-derived mitochondria resulted in CiCMs with a higher oxygen consumption rate capacity, enhanced electrical functionality, and higher sensitivity to hypoxic condition. These results are related to metabolic changes caused by increased number and size of mitochondria and activated mitochondrial fusion after mitochondrial treatment. In conclusion, our study suggests that mitochondrial delivery into CiCMs can be an effective strategy to promote cellular maturation, potentially contributing to the advancement of regenerative medicine and disease modeling.
由于天然心脏恢复丢失的心肌细胞的能力有限，心脏退行性疾病构成了重大挑战。直接细胞重编程技术，特别是小分子的使用，已成为一种有前景的解决方案，可通过更快、更安全的过程制备功能性心肌细胞，而无需进行基因改造。然而，目前的直接重编程方法通常表现出低转化效率以及所生成的心肌细胞的不成熟特征，限制了它们在再生医学中的应用。本研究提出利用线粒体递送对化学诱导的心肌样细胞（CiCMs）进行代谢重编程，促进其成熟度和功能的增强。我们的研究结果表明，源自高能量需求器官（肝脏、大脑和心脏）的线粒体可增强结构成熟度和代谢功能。值得注意的是，心脏来源的线粒体使CiCMs具有更高的氧消耗率能力、增强的电功能以及对缺氧条件更高的敏感性。这些结果与线粒体处理后线粒体数量和大小增加以及线粒体融合激活所导致的代谢变化有关。总之，我们的研究表明，将线粒体递送至CiCMs中可能是促进细胞成熟的有效策略，这可能有助于再生医学和疾病建模的发展。
