Department of Pediatrics and Child Health, Nihon University School of Medicine, Tokyo, Japan.
Wata Clinic, Tokyo, Japan.
Cell Biol Int. 2021 Feb;45(2):295-304. doi: 10.1002/cbin.11487. Epub 2020 Oct 29.
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.
脂肪组织（EAT）与心肌组织之间的相互作用对于心力衰竭的发病机制非常重要。肥胖或糖尿病中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，前脂肪细胞分泌的促炎细胞因子比成熟脂肪细胞高。然而，尚未了解未分化细胞向脂肪谱系的直接影响心肌细胞的方式。我们使用源自人类的去分化脂肪（DFAT）细胞作为未分化细胞向脂肪谱系分化的模型。在这里，我们评估了可溶性因子相互作用对 DFAT 细胞和诱导多能干细胞衍生的心肌细胞间接共培养的影响。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功能，同时增加了细胞凋亡，降低了抗氧化应激能力，并降低了心肌细胞的耗氧量。这些不利影响可能归因于 DFAT 细胞分泌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、白细胞介素 6 和 8、巨噬细胞移动抑制因子（MIF）和纤溶酶原激活物抑制剂 1-A 等促炎介质。我们的研究结果有助于从涉及未分化细胞向脂肪谱系的角度理解 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作为一种策略的重要性，以最大限度地提高移植的干细胞衍生心肌细胞的存活率和功能。
