Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (L.S., E.G., M.J.B.-P.); Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain (L.S., E.G., M.M., B.P., G.A., F.P., M.J.B.-P.); Hematology and Cell Therapy, Clínica Universidad de Navarra and Foundation for Applied Medical Research, Pamplona, Spain (M.M., B.P., G.A., F.P.); Center of Regenerative Medicine in Barcelona (CRMB), Hospitalet de Llobregat, Barcelona, Spain, Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain (O.I.-G., A.R.) and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (A.R.).
Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain (L.S., E.G., M.J.B.-P.); Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain (L.S., E.G., M.M., B.P., G.A., F.P., M.J.B.-P.); Hematology and Cell Therapy, Clínica Universidad de Navarra and Foundation for Applied Medical Research, Pamplona, Spain (M.M., B.P., G.A., F.P.); Center of Regenerative Medicine in Barcelona (CRMB), Hospitalet de Llobregat, Barcelona, Spain, Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain (O.I.-G., A.R.) and Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain (A.R.)
J Pharmacol Exp Ther. 2019 Sep;370(3):761-771. doi: 10.1124/jpet.118.256065. Epub 2019 Feb 6.
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are a promising cell source for cardiac repair after myocardial infarction (MI) because they offer several advantages such as potential to remuscularize infarcted tissue, integration in the host myocardium, and paracrine therapeutic effects. However, cell delivery issues have limited their potential application in clinical practice, showing poor survival and engraftment after transplantation. In this work, we hypothesized that the combination of hiPSC-CMs with microparticles (MPs) could enhance long-term cell survival and retention in the heart and consequently improve cardiac repair. CMs were obtained by differentiation of hiPSCs by small-molecule manipulation of the Wnt pathway and adhered to biomimetic poly(lactic-co-glycolic acid) MPs covered with collagen and poly(d-lysine). The potential of the system to support cell survival was analyzed in vitro, demonstrating a 1.70-fold and 1.99-fold increase in cell survival after 1 and 4 days, respectively. The efficacy of the system was tested in a mouse MI model. Interestingly, 2 months after administration, transplanted hiPSC-CMs could be detected in the peri-infarct area. These cells not only maintained the cardiac phenotype but also showed in vivo maturation and signs of electrical coupling. Importantly, cardiac function was significantly improved, which could be attributed to a paracrine effect of cells. These findings suggest that MPs represent an excellent platform for cell delivery in the field of cardiac repair, which could also be translated into an enhancement of the potential of cell-based therapies in other medical applications.
人心肌细胞来源于人诱导多能干细胞（hiPSC-CMs），是心肌梗死后心脏修复的有前途的细胞来源，因为它们具有一些优势，如潜在的再肌化梗死组织、与宿主心肌整合和旁分泌治疗效果。然而，细胞输送问题限制了它们在临床实践中的潜在应用，显示出在移植后细胞的生存和植入能力较差。在这项工作中，我们假设将 hiPSC-CMs 与微粒（MPs）结合可以增强细胞在心脏中的长期生存和保留能力，从而改善心脏修复。通过小分子操纵 Wnt 通路对 hiPSC 进行分化获得 CMs，并附着在覆盖有胶原蛋白和聚（D-赖氨酸）的仿生聚（乳酸-共-羟基乙酸） MPs 上。该系统支持细胞生存的潜力在体外进行了分析，结果表明细胞在第 1 天和第 4 天的存活率分别提高了 1.70 倍和 1.99 倍。该系统的疗效在小鼠心肌梗死模型中进行了测试。有趣的是，给药后 2 个月，可以在梗死周围区域检测到移植的 hiPSC-CMs。这些细胞不仅保持了心脏表型，而且表现出体内成熟和电耦联的迹象。重要的是，心脏功能得到了显著改善，这可以归因于细胞的旁分泌作用。这些发现表明 MPs 代表了心脏修复领域细胞输送的一个极好平台，也可以转化为增强细胞疗法在其他医学应用中的潜力。
