iPSCs as a Platform for Disease Modeling, Drug Screening, and Personalized Therapy in Muscular Dystrophies

Abstract

Induced pluripotent stem cells (iPSCs) are the foundation of modern stem cell-based regenerative medicine, especially in the case of degenerative disorders, such as muscular dystrophies (MDs). Since their introduction in 2006, many studies have used iPSCs for disease modeling and identification of involved mechanisms, drug screening, as well as gene correction studies. In the case of muscular dystrophies, these studies commenced in 2008 and continue to address important issues, such as defining the main pathologic mechanisms in different types of MDs, drug screening to improve skeletal/cardiac muscle cell survival and to slow down disease progression, and evaluation of the efficiency of different gene correction approaches, such as exon skipping, Transcription activator-like effector nucleases (TALENs), Zinc finger nucleases (ZFNs) and RNA-guided endonuclease Cas9 (CRISPR/Cas9). In the current short review, we have summarized chronological progress of these studies and their key findings along with a perspective on the future road to successful iPSC-based cell therapy for MDs and the potential hurdles in this field.

Versatility of Induced Pluripotent Stem Cells (iPSCs) for Improving the Knowledge on Musculoskeletal Diseases

“…So far, different groups have demonstrated the suitability of iPSCs to derive large quantities of myogenic precursors [ 116 ] and to model MDs as reviewed elsewhere [ 5 ]. MDs are a spectrum of muscle disorders caused by a number of gene mutations [ 117 ].…”

“…In high-income countries, musculoskeletal conditions are one of the major causes of work loss and early retirement, lost retirement wealth [ 4 ] and reduced national productivity [ 4 ]. For instance, despite the fact that most of these disorders are not immediately life-threatening, some of them have been proven to have higher mortality rates [ 2 , 5 ]. Although novel pharmacotherapies that improve survival and functioning have been developed for certain muscle diseases, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) or Pompe disease [ 6 ], there is no pharmacological treatment that can effectively cure most of these diseases.…”

“…Although novel pharmacotherapies that improve survival and functioning have been developed for certain muscle diseases, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA) or Pompe disease [ 6 ], there is no pharmacological treatment that can effectively cure most of these diseases. To date, most of the existing treatments aim to decrease pain and alleviating symptoms [ 5 , 7 ] but the therapeutic outcomes still need to be improved [ 3 ].…”

The past, present and future of Dictyostelium as a model system

“…New genetic tools, such as CRISPR/Cas9, have made mammalian and human cells accessible to genetic manipulation and editing, reducing the genetic gap with lower model organisms. Furthermore, disease modelling can be done with increasing effectiveness using human induced pluripotent stem cells or 3-D organoids (Wang et al, 2019;Chen and Knoepfler 2016;Robbins and Price, 2017;Dutta et al, 2017;Ortiz-Vitali and Darabi, 2019). In view of these developments, and in consideration of the increased competitiveness and pressure for research funding, it is difficult to anticipate what could be the future of Dictyostelium as a model organism.…”

Multilineage Differentiation for Formation of Innervated Skeletal Muscle Fibers from Healthy and Diseased Human Pluripotent Stem Cells

“…Since the discovery in Human of somatic cell reprogramming into pluripotent stem cells (hiPSCs), protocols aimed at modeling skeletal muscle differentiation have been lagging behind those of other cell lineages [1].…”