Peters Marijn C, Di Martino Sofia, Boelens Thomas, Qin Jiabin, van Mil Alain, Doevendans Pieter A, Chamuleau Steven A J, Sluijter Joost P G, Neef Klaus
Department of Cardiology, Laboratory of Experimental Cardiology, Regenerative Medicine Centre Utrecht, University Medical Centre Utrecht, University Utrecht, 3584 CX Utrecht, the Netherlands.
Department of Cardiology, Amsterdam Medical Centre, 1105 AZ Amsterdam, the Netherlands.
Mol Ther Methods Clin Dev. 2022 Feb 23;25:3-16. doi: 10.1016/j.omtm.2022.02.005. eCollection 2022 Jun 9.
The human heart has limited regenerative capacity. Therefore, patients often progress to heart failure after ischemic injury, despite advances in reperfusion therapies generally decreasing mortality. Depending on its glycosylation state, Follistatin-like 1 (FSTL1) has been shown to increase cardiomyocyte (CM) proliferation, decrease CM apoptosis, and prevent cardiac rupture in animal models of ischemic heart disease. To explore its therapeutic potential, we used a human model of cardiac ischemic injury with human induced pluripotent stem cell-derived CMs (iPSC-CMs) and assessed regenerative effects of two differently glycosylated variants of human FSTL1. Furthermore, we investigated the FSTL1-mediated interplay between human cardiac fibroblasts (cFBs) and iPSC-CMs in hypoxia. Both FSTL1 variants increased viability, while only hypo-glycosylated FSTL1 increased CM proliferation post-hypoxia. Human fetal cardiac fibroblasts (fcFBs) expressed and secreted FSTL1 under normoxic conditions, while FSTL1 secretion increased by iPSC-cFBs upon hypoxia but decreased in iPSC-CMs. Co-culture of iPSC-CMs and cFBs increased FSTL1 secretion compared with cFB mono-culture. Taken together, we confirm that FSTL1 induces iPSC-CM proliferation in a human cardiac hypoxia damage model. Furthermore, we show hypoxia-related FSTL1 secretion by human cFBs and indications for FSTL1-mediated intercellular communication between cardiac cell types in response to hypoxic conditions.
人类心脏的再生能力有限。因此，尽管再灌注疗法的进展总体上降低了死亡率，但患者在缺血性损伤后仍常发展为心力衰竭。根据其糖基化状态，卵泡抑素样蛋白1（FSTL1）已被证明在缺血性心脏病动物模型中可增加心肌细胞（CM）增殖、减少CM凋亡并防止心脏破裂。为了探索其治疗潜力，我们使用了一种含有人类诱导多能干细胞衍生的CM（iPSC-CM）的心脏缺血性损伤人类模型，并评估了两种不同糖基化变体的人类FSTL1的再生作用。此外，我们研究了FSTL1介导的人类心脏成纤维细胞（cFB）与iPSC-CM在缺氧状态下的相互作用。两种FSTL1变体均提高了细胞活力，而只有低糖基化的FSTL1在缺氧后增加了CM增殖。人类胎儿心脏成纤维细胞（fcFB）在常氧条件下表达并分泌FSTL1，而iPSC-cFB在缺氧时FSTL1分泌增加，但在iPSC-CM中减少。与cFB单培养相比，iPSC-CM与cFB共培养增加了FSTL1分泌。综上所述，我们证实FSTL1在人类心脏缺氧损伤模型中诱导iPSC-CM增殖。此外，我们展示了人类cFB在缺氧相关情况下FSTL1的分泌情况，以及FSTL1介导的心脏细胞类型之间在缺氧条件下的细胞间通讯迹象。
