Soluble factors released by dedifferentiated fat cells reduce the functional activity of iPS cell-derived cardiomyocytes
Soluble factors released by dedifferentiated fat cells reduce the functional activity of iPS cell-derived cardiomyocytes
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去分化脂肪细胞释放的可溶性因子降低 iPS 细胞来源的心肌细胞的功能活性
DOI：
10.1002/cbin.11487
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发表时间：
2021
影响因子：
3.9
通讯作者：
I.
中科院分区：
文献类型：
--
作者：
Watanabe;H.;Kanemaru;K.;Hagikura;K.;Matsumoto;T.;Ayusawa;M.;& Morioka;I.
心外膜脂肪(EAT)等组织与心肌组织之间的相互作用在心力衰竭的发病机制中具有重要意义。肥胖或糖尿病时脂肪组织的变化会损害前脂肪细胞的分化。此外，在糖尿病和肥胖症中，前脂肪细胞的促炎细胞因子分泌高于成熟脂肪细胞。然而，致力于脂肪谱系的未分化细胞如何直接影响心肌细胞尚不清楚。我们使用人源性去分化脂肪(DFAT)细胞作为致力于脂肪谱系的未分化细胞的模型。在这里，我们评估了DFAT细胞间接共培养和诱导多能干细胞来源的心肌细胞中可溶性因子相互作用的影响。我们的RNA测序结果表明，这些相互作用主要是炎症反应。此外，DFAT细胞分泌的促炎细胞因子降低了心肌细胞的收缩频率和儿茶酚胺敏感性等心肌功能，同时增加了心肌细胞的凋亡率，降低了抗氧化应激耐受性，降低了心肌细胞的耗氧率。这些不良反应可能与DFAT细胞分泌的促炎介质中的单核细胞趋化蛋白-1、趋化因子(C-X-C基序)配体1(CXCL1)和12、粒细胞集落刺激因子、白介素6和8、巨噬细胞移动抑制因子(MIF)和纤溶酶原激活物抑制物1-A有关。我们的结果可能有助于从致力于脂肪谱系的未分化细胞的参与来理解EAT相关心力衰竭的发病机制。此外，我们建议关注周围脂肪组织的重要性，以此作为最大化干细胞来源的移植心肌细胞存活和功能的策略。
Interactions between tissues such as epicardial adipose (EAT), and myocardial tissues is important in the pathogenesis of heart failure. Changes in adipose tissues in obesity or diabetes impair preadipocyte differentiation. Furthermore, proinflammatory cytokine secretion is higher in preadipocytes than in mature adipocytes in diabetes and obesity. However, how undifferentiated cells committed to the adipose lineage directly influence cardiomyocytes is not yet understood. We used human‐derived dedifferentiated fat (DFAT) cells as models of undifferentiated cells committed to an adipose lineage. Here, we evaluated the effects of soluble factor interactions in indirect cocultures of DFAT cells and induced pluripotent stem cell‐derived cardiomyocytes.Our RNA sequencing findings showed that these interactions were predominantly inflammatory responses. Furthermore, proinflammatory cytokines secreted by DFAT cells reduced myocardial functions such as contraction frequency and catecholamine sensitivity, and simultaneously increased apoptosis, decreased antioxidative stress tolerance, and reduced oxygen consumption rates in cardiomyocytes. These adverse effects might be attributable to monocyte chemoattractant protein‐1, chemokine (C‐X‐C motif) ligands 1 (CXCL1), and 12, granulocyte colony‐stimulating factor, interleukins 6 and 8, macrophage migration inhibitory factor (MIF), and plasminogen activator inhibitor 1‐A among the proinflammatory mediators secreted by DFAT cells. Our results could be useful for understanding the pathogenesis of EAT‐related heart failure in terms of the involvement of undifferentiated cells committed to the adipose lineage. Furthermore, we suggest the importance of focusing on surrounding adipose tissues as a strategy with which to maximize the survival and function of transplanted stem cell‐derived cardiomyocytes.