Department of Molecular Pathology, The University of Texas M D Anderson Cancer Center, SCRB2, Houston, TX 77054, USA.
Mol Imaging Biol. 2011 Aug;13(4):633-45. doi: 10.1007/s11307-010-0392-z.
PURPOSE: Transplantation of a regenerative cell population derived from human subcutaneous adipose tissue (hASCs) for cardiac regeneration represents a promising therapy due to the capacity of these cells for proliferation and differentiation. Understanding the fate of injected hASCs would help to understand how hASCs work in vivo. The aim of this study was to track the long-term fate, including survival, differentiation, proliferation, apoptosis, migration, and growth factor secretion of intramyocardially injected hASCs following experimental acute myocardial infarction in an immunodeficient mouse model. METHODS: Myocardial infarction was experimentally induced in severe combined immunodeficient mice by permanent ligation of the left anterior descending coronary artery. Lentivirally labeled hASCs (5 × 10(5); expressing green fluorescence protein [GFP] and luciferase) were injected into the peri-infarct region. Colony formation, growth kinetics, and differentiation of transduced hASCs were analyzed in vitro and compared to those of untransduced hASCs. The survival and migration of injected hASCs were tracked by luciferase-based bioluminescence imaging for 10 weeks. Immunofluorescence and terminal deoxynucleotidyl transferase dUTP nick end labeling staining were used to assess differentiation, proliferation, growth factor expression, or apoptosis of grafted hASCs in infarcted hearts and potential distribution to other tissues. RESULTS: Lentivirus transduction and GFP and luciferase expression did not influence proliferation or differentiation of hASCs. Bioluminescence imaging demonstrated that injected hASCs survived in infarcted hearts during the follow-up of 10 weeks. Immunofluorescence confirmed that hASCs engrafted in ischemic hearts expressed bFGF and IGF-1, and did not migrate into other organs. Of all engrafted hASCs, 3.5% differentiated into cardiomyocytes or endothelial cells. Other cells maintained their proliferative potential or underwent apoptosis. CONCLUSION: Luciferase-based bioluminescence imaging allows long-term tracking of intramyocardially injected hASCs in living mice. The hASCs might enhance function of injured hearts through long-term engraftment, growth factor secretion, and transdifferentiation to cardiomyocytes and endothelial cells.
目的：源自人皮下脂肪组织（hASCs）的再生细胞群体的移植用于心脏再生代表了一种有前途的治疗方法，因为这些细胞具有增殖和分化的能力。了解注射的 hASC 的命运将有助于了解 hASC 在体内的作用。本研究的目的是在免疫缺陷小鼠模型中通过永久性结扎左前降支冠状动脉来诱导实验性急性心肌梗死，以追踪心肌内注射的 hASC 的长期命运，包括存活、分化、增殖、凋亡、迁移和生长因子分泌。
方法：通过永久性结扎左前降支冠状动脉在严重联合免疫缺陷小鼠中诱导心肌梗死。将慢病毒标记的 hASC（5×10（5）; 表达绿色荧光蛋白[GFP]和荧光素酶）注射到梗死周围区域。在体外分析转导的 hASC 的集落形成、生长动力学和分化，并与未转导的 hASC 进行比较。通过基于荧光素酶的生物发光成像在 10 周内追踪注射的 hASC 的存活和迁移。免疫荧光和末端脱氧核苷酸转移酶 dUTP 缺口末端标记染色用于评估移植 hASC 在梗死心脏中的分化、增殖、生长因子表达或凋亡以及潜在的分布到其他组织。
结果：慢病毒转导和 GFP 和荧光素酶表达不影响 hASC 的增殖或分化。生物发光成像显示，在 10 周的随访期间，注射的 hASC 在梗死心脏中存活。免疫荧光证实，在缺血心脏中移植的 hASC 表达 bFGF 和 IGF-1，并且不会迁移到其他器官。所有移植的 hASC 中，有 3.5%分化为心肌细胞或内皮细胞。其他细胞保持其增殖潜能或发生凋亡。
结论：基于荧光素酶的生物发光成像允许在活小鼠中对心肌内注射的 hASC 进行长期追踪。hASC 可能通过长期植入、生长因子分泌以及向心肌细胞和内皮细胞的转分化来增强受损心脏的功能。
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