Freeman Brian T, Kouris Nicholas A, Ogle Brenda M
Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation, and Material Sciences Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation, and Material Sciences Program, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA
Stem Cells Transl Med. 2015 Jun;4(6):685-94. doi: 10.5966/sctm.2014-0198. Epub 2015 Apr 6.
Evidence suggests that transplanted mesenchymal stem cells (MSCs) can aid recovery of damaged myocardium caused by myocardial infarction. One possible mechanism for MSC-mediated recovery is reprogramming after cell fusion between transplanted MSCs and recipient cardiac cells. We used a Cre/LoxP-based luciferase reporter system coupled to biophotonic imaging to detect fusion of transplanted human pluripotent stem cell-derived MSCs to cells of organs of living mice. Human MSCs, with transient expression of a viral fusogen, were delivered to the murine heart via a collagen patch. At 2 days and 1 week later, living mice were probed for bioluminescence indicative of cell fusion. Cell fusion was detected at the site of delivery (heart) and in distal tissues (i.e., stomach, small intestine, liver). Fusion was confirmed at the cellular scale via fluorescence in situ hybridization for human-specific and mouse-specific centromeres. Human cells in organs distal to the heart were typically located near the vasculature, suggesting MSCs and perhaps MSC fusion products have the ability to migrate via the circulatory system to distal organs and engraft with local cells. The present study reveals previously unknown migratory patterns of delivered human MSCs and associated fusion products in the healthy murine heart. The study also sets the stage for follow-on studies to determine the functional effects of cell fusion in a model of myocardial damage or disease.
Mesenchymal stem cells (MSCs) are transplanted to the heart, cartilage, and other tissues to recover lost function or at least limit overactive immune responses. Analysis of tissues after MSC transplantation shows evidence of fusion between MSCs and the cells of the recipient. To date, the biologic implications of cell fusion remain unclear. A newly developed in vivo tracking system was used to identify MSC fusion products in living mice. The migratory patterns of fusion products were determined both in the target organ (i.e., the heart) and in distal organs. This study shows, for the first time, evidence of fusion products at sites distal from the target organ and data to suggest that migration occurs via the vasculature. These results will inform and improve future, MSC-based therapeutics.
有证据表明，移植的间充质干细胞（MSC）有助于心肌梗死所致受损心肌的恢复。MSC介导恢复的一种可能机制是移植的MSC与受体心脏细胞之间发生细胞融合后进行重编程。我们使用基于Cre/LoxP的荧光素酶报告系统结合生物光子成像来检测移植的人多能干细胞衍生的MSC与活体小鼠器官细胞的融合。通过胶原贴片将瞬时表达病毒融合蛋白的人MSC递送至小鼠心脏。在2天和1周后，对活体小鼠进行探测以检测指示细胞融合的生物发光。在递送部位（心脏）和远端组织（即胃、小肠、肝脏）检测到细胞融合。通过针对人特异性和小鼠特异性着丝粒的荧光原位杂交在细胞水平上证实了融合。心脏远端器官中的人细胞通常位于血管附近，这表明MSC以及可能的MSC融合产物有能力通过循环系统迁移至远端器官并与局部细胞植入。本研究揭示了递送的人MSC及其相关融合产物在健康小鼠心脏中以前未知的迁移模式。该研究还为后续研究奠定了基础，以确定细胞融合在心肌损伤或疾病模型中的功能作用。
间充质干细胞（MSC）被移植到心脏、软骨和其他组织以恢复失去的功能或至少限制过度活跃的免疫反应。MSC移植后组织分析显示有MSC与受体细胞融合的证据。迄今为止，细胞融合的生物学意义仍不清楚。一种新开发的体内追踪系统用于识别活体小鼠中的MSC融合产物。确定了融合产物在靶器官（即心脏）和远端器官中的迁移模式。本研究首次显示了在靶器官远端部位存在融合产物的证据以及表明迁移通过血管系统发生的数据。这些结果将为未来基于MSC的治疗提供信息并加以改进。
