Asadi-Sarabi Pedram, Rismani Elham, Shabanpouremam Mahshid, Hendi Zahra, Nikoubin Behnaz, Rahimi Saina, Taleb Mohammad, Khosravi Arezoo, Zarrabi Ali, Hassan Moustapha, Vosough Massoud
Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
Molecular Medicine Department, Biotechnology Research Center (BRC), Pasteur Institute of Iran, Tehran, Iran.
Int Immunopharmacol. 2025 Sep 23;162:115134. doi: 10.1016/j.intimp.2025.115134. Epub 2025 Jun 27.
Hypoimmunogenic pluripotent stem cells (hPSCs) represent a transformative innovation in regenerative medicine, offering solutions to the longstanding challenge of immune rejection in cell-based therapies. Through advanced gene-editing techniques, particularly CRISPR/Cas9, hPSCs are engineered to downregulate or eliminate the expression of major histocompatibility complex (MHC) molecules while upregulating immunomodulatory proteins such as HLA-G, PD-L1, and CD47. These modifications enhance immune evasion and create the foundation for universal donor cells. Compared to conventional cell therapies that rely on lifelong immunosuppression, hPSC-based strategies offer safer, more sustainable, and patient-friendly solutions by minimizing the risks of infection, malignancy, and drug toxicity. Beyond immune compatibility, critical challenges persist, including the risk of tumorigenicity, off-target genetic alterations, and ethical considerations surrounding genome editing. Recent advances, such as the integration of suicide gene systems and sensitive monitoring assays, offer promising strategies to enhance the safety and functional stability of hPSC-derived therapies. This review comprehensively discusses the molecular engineering of hPSCs, their biomedical applications, safety strategies, ethical implications, and the evolving regulatory frameworks needed for clinical translation. By addressing both the scientific and societal dimensions, hPSCs have the potential to revolutionize personalized and off-the-shelf regenerative treatments, provided that rigorous safeguards are implemented.
低免疫原性多能干细胞（hPSC）代表了再生医学中的一项变革性创新，为基于细胞的疗法中长期存在的免疫排斥挑战提供了解决方案。通过先进的基因编辑技术，特别是CRISPR/Cas9，对hPSC进行工程改造，以下调或消除主要组织相容性复合体（MHC）分子的表达，同时上调免疫调节蛋白，如HLA-G、PD-L1和CD47。这些修饰增强了免疫逃逸能力，为通用供体细胞奠定了基础。与依赖终身免疫抑制的传统细胞疗法相比，基于hPSC的策略通过将感染、恶性肿瘤和药物毒性风险降至最低，提供了更安全、更可持续且对患者更友好的解决方案。除了免疫相容性之外，关键挑战依然存在，包括致瘤风险、脱靶基因改变以及围绕基因组编辑的伦理考量。最近的进展，如自杀基因系统的整合和灵敏的监测检测方法，为提高hPSC衍生疗法的安全性和功能稳定性提供了有前景的策略。本综述全面讨论了hPSC的分子工程、其生物医学应用、安全策略、伦理影响以及临床转化所需的不断演变的监管框架。通过兼顾科学和社会层面，只要实施严格的保障措施，hPSC就有潜力彻底改变个性化和现成可用的再生治疗方法。
