Department of Stem Cell Biology, Centre for Biomolecular Sciences, University of Nottingham, UK.
Dubowitz Neuromuscular Centre, Department of Molecular Neurosciences, University College London - Institute of Child Health, London, UK.
J Neuromuscul Dis. 2016 Aug 30;3(3):309-332. doi: 10.3233/JND-150133.
Muscular dystrophies (MDs) are clinically and molecularly a highly heterogeneous group of single-gene disorders that primarily affect striated muscles. Cardiac disease is present in several MDs where it is an important contributor to morbidity and mortality. Careful monitoring of cardiac issues is necessary but current management of cardiac involvement does not effectively protect from disease progression and cardiac failure. There is a critical need to gain new knowledge on the diverse molecular underpinnings of cardiac disease in MDs in order to guide cardiac treatment development and assist in reaching a clearer consensus on cardiac disease management in the clinic. Animal models are available for the majority of MDs and have been invaluable tools in probing disease mechanisms and in pre-clinical screens. However, there are recognized genetic, physiological, and structural differences between human and animal hearts that impact disease progression, manifestation, and response to pharmacological interventions. Therefore, there is a need to develop parallel human systems to model cardiac disease in MDs. This review discusses the current status of cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC) to model cardiac disease, with a focus on Duchenne muscular dystrophy (DMD) and myotonic dystrophy (DM1). We seek to provide a balanced view of opportunities and limitations offered by this system in elucidating disease mechanisms pertinent to human cardiac physiology and as a platform for treatment development or refinement.
肌肉萎缩症(MDs)是一组临床和分子上高度异质的单基因疾病,主要影响横纹肌。几种 MD 都存在心脏疾病,它是发病率和死亡率的重要因素。需要仔细监测心脏问题,但目前对心脏受累的管理并不能有效地防止疾病进展和心力衰竭。为了指导心脏治疗的发展,并协助在临床上对心脏疾病的管理达成更明确的共识,迫切需要获得关于 MD 中心脏疾病的不同分子基础的新知识。大多数 MD 都有动物模型,这些模型是研究疾病机制和临床前筛选的宝贵工具。然而,人类和动物心脏之间存在公认的遗传、生理和结构差异,这些差异会影响疾病的进展、表现和对药物干预的反应。因此,需要开发平行的人类系统来模拟 MD 中的心脏疾病。这篇综述讨论了源自人类诱导多能干细胞(hiPSC)的心肌细胞(CMs)用于模拟心脏疾病的现状,重点讨论了杜氏肌营养不良症(DMD)和强直性肌营养不良症(DM1)。我们试图提供一个平衡的观点,说明该系统在阐明与人类心脏生理学相关的疾病机制以及作为治疗开发或改进的平台方面提供的机会和限制。