Development and validation of a novel bioprinted, human-diabetic cardiac organoid model

心肌病是2型糖尿病的一种使人衰弱的并发症，易使患者患病 由于心脏肌肉功能紊乱而导致心力衰竭风险增加 它能够有效地使血液在体内循环，并保持正常的电子节律。 尽管它具有巨大的临床影响，但缺乏针对糖尿病的有针对性的治疗方案。 由于药物筛选条件的复杂病理生理学引起的心肌病 这是个问题。目前的治疗策略是根据动物实验结果制定的 实验中，不能很好地在体内转化为人类。因此，研究的基础应该是 从人类诱导的多能干细胞中分离出的实验室工程心脏组织模型 细胞(IPSC)分化的心肌细胞是保存体内生理所必需的，以及 模仿疾病的发展。但是，缺乏这样的基于临床前人体组织的模型来 建立一个筛选平台，以确定将保存的潜在疗法 糖尿病应激时心脏细胞的生理和功能。为了满足这一需求，我们 将开发一种独特的“心脏器官”系统，该系统将使用人类的生物打印来组装 心肌细胞，包括心肌细胞(CM)、成纤维细胞(CF)和内皮细胞(EC)， 专门从糖尿病捐赠者那里获得。生物打印将能够创造一个环境 培养与生理相关的线索的发展，从而产生功能组织 建造时要保持适当的一致性。来自糖尿病捐赠者的细胞将保留他们的疾病 表型或‘代谢记忆’，这将是有价值的观察和研究它们的结构和 暴露在高血糖环境中时的功能变化。人类IPSC来源 2型糖尿病供体将被定制为CM，并与CF和EC混合用于 生物打印将暴露在正常和高血糖条件下的‘心脏器官’，以 描述代谢性记忆、高血糖及其组合所造成的影响 两者都有。研究结果将有助于理解信号通路在疾病中的作用 进展，这可能会指导和告知我们设计一种增强的治疗方法 从高血糖损伤中抢救心脏组织的方法。圆满完成 这些研究将导致建立针对患者的人类2型IPSC模型。 糖尿病，并揭示了这种方法在发现新的治疗策略方面的力量 代谢状态复杂，临床意义上升。

Cardiomyopathy is a debilitating complication of type-2 diabetes that predisposes patients towards increased risk of heart failure due to the disorder of the heart muscle that compromises its ability to circulate blood through the body and maintain a normal electrical rhythm, effectively. Despite its immense clinical impact, there is a lack of targeted treatment regimen for diabetic cardiomyopathy due to the intricate pathophysiology of the condition that makes drug screening problematic. Current therapeutic strategies developed on results originating from animal experiments, do not transform well to humans in vivo. Hence, studies should be based on laboratory engineered ‘cardiac tissue’ models biofabricated from human induced pluripotent stem cell (iPSC) differentiated cardiomyocytes that are essential to preserve in vivo physiology, and mimic disease progression. But, there is lack of such preclinical human tissue based models to establish a screening platform for the identification of potential therapeutics that will preserve cardiac cell physiology and function when exposed to diabetic stress. To address this need, we will develop a unique ‘cardiac organoid’ system that will be assembled using bioprinting of human cardiac cells, including cardiomyocytes (CM), fibroblasts (CF) and endothelial cells (EC), specifically sourced from diabetic donors. Bioprinting will enable the creation of an environment to nurture the development of physiologically relevant cues, resulting in a functional tissue construct with appropriate consistency. Cells derived from diabetic donors will retain their disease phenotype or `metabolic memory', which will be valuable to observe and study their structural and functional changes when exposed to hyperglycemic environments. Human iPSC sourced from type-2 diabetic donors will be custom differentiated into CM and mixed with CF and EC for bioprinting of ‘cardiac organoids’ that will be exposed to normal and hyperglycemic conditions to delineate between the effects caused by metabolic memory, hyperglycemia and a combination of both. Results will help in understanding the role of the signaling pathways involved in disease progression, which may guide and inform us towards designing an enhanced therapeutic approach for rescuing cardiac tissues from hyperglycemic insult. The successful completion of these studies will lead to establishment of a patient-specific iPSC model of human type-2- diabetes, and reveal the power of this approach for discovery of new therapeutic strategies for a complex metabolic condition with rising clinical significance.