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， 由于心脏肌肉的紊乱而导致心力衰竭的风险增加， 它能够有效地使血液在体内循环并维持正常的电节律。 尽管其具有巨大的临床影响，但缺乏针对糖尿病的靶向治疗方案。 心肌病由于复杂的病理生理条件，使药物筛选 有问题目前的治疗策略是根据动物源性结果开发的 在实验中，在体内不能很好地转化为人类。因此，研究应基于 从人类诱导多能干细胞生物制造的实验室工程化“心脏组织”模型 细胞（iPSC）分化的心肌细胞，其对于保持体内生理学是必需的，和 模拟疾病进展。但是，缺乏这样的临床前基于人体组织的模型， 建立一个筛选平台，以确定潜在的治疗方法， 心脏细胞生理学和功能时暴露于糖尿病应激。为了满足这一需求，我们 将开发一种独特的“心脏类器官”系统，该系统将使用人类的生物打印进行组装。 心肌细胞，包括心肌细胞（CM）、成纤维细胞（CF）和内皮细胞（EC）， 特别是来自糖尿病捐赠者。生物打印将创造一个环境， 培养生理相关线索的发展，导致功能组织 保持适当的一致性。来自糖尿病供体的细胞将保留其疾病 表型或“代谢记忆”，这将是有价值的观察和研究其结构和 当暴露于高血糖环境时功能改变。人iPSC来源于 2型糖尿病供体将定制分化成CM并与CF和EC混合， 生物打印将暴露于正常和高血糖条件下的“心脏类器官”， 描述代谢记忆、高血糖症和以下因素的组合引起的影响： 两者结果将有助于了解参与疾病的信号通路的作用 进展，这可能会指导和告知我们设计一种增强的治疗方法， 从高血糖损伤中拯救心脏组织的方法。圆满完成 这些研究将导致建立人2型的患者特异性iPSC模型， 糖尿病，并揭示了这种方法的力量，为发现新的治疗策略， 复杂的代谢状况，临床意义日益增加。

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.