Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders

Qin, Yiren; Gao, Wei‐Qiang

doi:10.1002/stem.2112

Cited by 13 publications

(18 citation statements)

References 198 publications

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“…MGDs caused by single gene mutations have serious effects on human health 19 . β-Thalassemia is one of the most common MGD-associated diseases and represents more than 200 types of mutants in HBB gene-induced blood disorders 20 .…”

Section: Discussionmentioning

confidence: 99%

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection

Liu

Yang

Kang

et al. 2017

Molecular Therapy - Nucleic Acids

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Monogenic disorders (MGDs), which are caused by single gene mutations, have a serious effect on human health. Among these, β-thalassemia (β-thal) represents one of the most common hereditary hematological diseases caused by mutations in the human hemoglobin β (HBB) gene. The technologies of induced pluripotent stem cells (iPSCs) and genetic correction provide insights into the treatments for MGDs, including β-thal. However, traditional approaches for correcting mutations have a low efficiency and leave a residual footprint, which leads to some safety concerns in clinical applications. As a proof of concept, we utilized single-strand oligodeoxynucleotides (ssODNs), high-fidelity CRISPR/Cas9 nuclease, and small molecules to achieve a seamless correction of the β-41/42 (TCTT) deletion mutation in β thalassemia patient-specific iPSCs with remarkable efficiency. Additionally, off-target analysis and whole-exome sequencing results revealed that corrected cells exhibited a minimal mutational load and no off-target mutagenesis. When differentiated into hematopoietic progenitor cells (HPCs) and then further to erythroblasts, the genetically corrected cells expressed normal β-globin transcripts. Our studies provide the most efficient and safe approach for the genetic correction of the β-41/42 (TCTT) deletion in iPSCs for further potential cell therapy of β-thal, which represents a potential therapeutic avenue for the gene correction of MGD-associated mutants in patient-specific iPSCs.

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Section: Discussionmentioning

confidence: 99%

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection

Liu

Yang

Kang

et al. 2017

Molecular Therapy - Nucleic Acids

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“…The recapitulation of the pathological phenotypes using disease-specific hiPSCs that can be differentiated in vitro, sets the basis for studying the aetiopathology of diseases, especially those in which the target cells are really inaccessible [11,12]. In a previous work we described a perturbed pattern of microRNA expression when comparing neural progenitor cells derived from the spinal cords of E13.5 SMA mice to WT.…”

Section: Discussionmentioning

confidence: 99%

SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression

Murdocca

Ciafrè

Spitalieri

et al. 2016

IJMS

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Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by mutations in the Survival Motor Neuron 1 gene, resulting in very low levels of functional Survival of Motor Neuron (SMN) protein. SMA human induced Pluripotent Stem Cells (hiPSCs) represent a useful and valid model for the study of the disorder, as they provide in vitro the target cells. MicroRNAs (miRNAs) are often reported as playing a key role in regulating neuronal differentiation and fate specification. In this study SMA hiPSCs have been differentiated towards early motor neurons and their molecular and immunocytochemical profile were compared to those of wild type cells. Cell cycle proliferation was also evaluated by fluorescence-activated cell sorting (FACS). SMA hiPSCs showed an increased proliferation rate and also higher levels of stem cell markers. Moreover; when differentiated towards early motor neurons they expressed lower levels of NCAM and MN specific markers. The expression of miR-335-5p; already identified to control self-renewal or differentiation of mouse embryonic stem cells (mESCs); resulted to be reduced during the early steps of differentiation of SMA hiPSCs compared to wild type cells. These results suggest that we should speculate a role of this miRNA both in stemness characteristic and in differentiation efficiency of these cells.

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“…Although the generation of iPSCs as cellular tool was reported for some disorders [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], this is the first time that NLSDM-iPSCs have been derived from fibroblasts of NLSDM patients. Cellular studies are needed to understand the pathophysiological mechanism of NLSDM and to develop personalized treatments that might increase fat mobilization and improve organ function.…”

Section: Discussionmentioning

confidence: 94%

“…Induced pluripotent stem cells (iPSCs) are a new technology which can provide an unlimited number of human disease-affected stem cells [16], [17], [18], [19], [20], [21]. These cells can theoretically differentiate into any cell type.…”

Section: Introductionmentioning

confidence: 99%

Generation of induced Pluripotent Stem Cells as disease modelling of NLSDM

Tavian

Missaglia

Castagnetta

et al. 2017

Molecular Genetics and Metabolism

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Neutral Lipid Storage Disease with Myopathy (NLSDM) is a rare defect of triacylglycerol metabolism, characterized by the abnormal storage of neutral lipid in organelles known as lipid droplets (LDs). The main clinical features are progressive myopathy and cardiomyopathy. The onset of NLSDM is caused by autosomal recessive mutations in the PNPLA2 gene, which encodes adipose triglyceride lipase (ATGL). Despite its name, this enzyme is present in a wide variety of cell types and catalyzes the first step in triacylglycerol lipolysis and the release of fatty acids.Here, we report the derivation of NLSDM-induced pluripotent stem cells (NLSDM-iPSCs) from fibroblasts of two patients carrying different PNPLA2 mutations. The first patient was homozygous for the c.541delAC, while the second was homozygous for the c.662G > C mutation in the PNPLA2 gene. We verified that the two types of NLSDM-iPSCs possessed properties of embryonic-like stem cells and could differentiate into the three germ layers in vitro. Immunofluorescence analysis revealed that iPSCs had an abnormal accumulation of triglycerides in LDs, the hallmark of NLSDM. Furthermore, NLSDM-iPSCs were deficient in long chain fatty acid lipolysis, when subjected to a pulse chase experiment with oleic acid. Collectively, these results demonstrate that NLSDM-iPSCs are a promising in vitro model to investigate disease mechanisms and screen drug compounds for NLSDM, a rare disease with few therapeutic options.

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Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders

Cited by 13 publications

References 198 publications

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection

One-Step Biallelic and Scarless Correction of a β-Thalassemia Mutation in Patient-Specific iPSCs without Drug Selection

SMA Human iPSC-Derived Motor Neurons Show Perturbed Differentiation and Reduced miR-335-5p Expression

Generation of induced Pluripotent Stem Cells as disease modelling of NLSDM

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