Van Orman Jordan R, Weihrauch Dorothee, Warltier David C, Lough John
Department of Cell Biology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1369-76. doi: 10.1152/ajpheart.00172.2009. Epub 2009 Jul 24.
Several recent studies have demonstrated that the transplantation of pluripotent murine embryonic stem cells (mESCs) can improve or restore the function of infarcted myocardium. Although the extent of remuscularization and its contribution to the restoration of function are unclear, these outcomes are likely strongly influenced by factors in the infarcted and/or ischemic environment. As an initial step toward understanding how the ischemic environment of host myocardium affects transplanted pluripotent cells, we have taken a reductionist approach wherein mESCs are cultured in medium containing ischemic myocardial interstitial fluid (iMIF). iMIF is generated in canine myocardium during eight hourly episodes of transient ischemia and collected on a daily basis, over a 24-day collection period. iMIF strongly reduced the numbers of pluripotent mESCs after 11 days in culture. This inhibitory effect, which was most pronounced for iMIF pools from early time points of the 24-day collection period, resulted from an inhibition of cell proliferation. iMIF also inhibited the differentiation of pluripotent mESCs into cardiomyocytes. By contrast, the expression of vascular smooth muscle and endothelial cell markers was relatively unaffected, consistent with previous findings that iMIF promotes angiogenesis. Taken together, these results suggest that whereas the ischemic/infarcted environment is favorable to stem cell-mediated angiogenesis, it is hostile to cardiac myogenesis. These findings also imply that observations of mESC-mediated improvement of cardiac function after transplantation of pluripotent cells do not reflect remuscularization.
最近的几项研究表明，多能性小鼠胚胎干细胞（mESCs）的移植可以改善或恢复梗死心肌的功能。尽管再肌化的程度及其对功能恢复的贡献尚不清楚，但这些结果可能受到梗死和/或缺血环境中多种因素的强烈影响。作为理解宿主心肌缺血环境如何影响移植的多能细胞的第一步，我们采用了一种简化方法，即将mESCs培养在含有缺血心肌间质液（iMIF）的培养基中。iMIF是在犬心肌短暂缺血的8小时期间产生的，并在24天的收集期内每天收集。培养11天后，iMIF显著减少了多能性mESCs的数量。这种抑制作用在24天收集期早期的iMIF样本中最为明显，是由细胞增殖抑制导致的。iMIF还抑制了多能性mESCs向心肌细胞的分化。相比之下，血管平滑肌和内皮细胞标志物的表达相对未受影响，这与之前iMIF促进血管生成的研究结果一致。综上所述，这些结果表明，虽然缺血/梗死环境有利于干细胞介导的血管生成，但对心肌生成具有抑制作用。这些发现还意味着，多能细胞移植后mESC介导的心脏功能改善并不反映再肌化。
