Amelioration of osteogenesis in iPSC-derived mesenchymal stem cells from osteogenesis imperfecta patients by endoplasmic reticulum stress inhibitor

Duangchan, Thitinat; Tawonsawatruk, Tulyapruek; Angsanuntsukh, Chanika; Trachoo, Objoon; Hongeng, Suradej; Kitiyanant, Narisorn; Supokawej, Aungkura

doi:10.1016/j.lfs.2021.119628

Cited by 16 publications

(10 citation statements)

References 81 publications

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“…iPSC‐derived MSCs can be used as a platform to examine new mechanisms of OI. ( 50 ) A meta‐analysis suggested that stem cell therapy alleviated OI phenotypes and exerted significant beneficial effects, such as reducing fracture incidence and increasing maximum load. ( 51 ) The CRISPR approach represents a promising therapeutic method for monogenic diseases caused either by recessive or dominant genetic mutations.…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9 correction of a dominant cis-double-variant in COL1A1 isolated from a patient with osteogenesis imperfecta increases the osteogenic capacity of induced pluripotent stem cells

Cao

Ren

et al. 2020

Journal of Bone and Mineral Research

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Osteogenesis imperfecta (OI) is a hereditary skeletal disorder that is mainly caused by variants in COL1A1/2. So far, no specific treatment has been developed to correct its underlying etiology. We aimed to gain a better understanding of the pathological mechanisms of OI and develop gene therapies to correct OI-causing variants. A de novel cis-double-variant c.[175C>T; 187T>A] in COL1A1 was identified from a 5-year-old OI patient by whole-exome sequencing (WES). Three peptide nucleic acids (PNAs) were designed and then transfected patient-derived fibroblasts. PNA2 affected the translational strand and induced an optimal interfering effect at 0.25μM concentration, proved by Sanger sequencing, qPCR, Western blot, and immunostaining. Additionally, induced pluripotent stem cells (iPSCs) were cultured from patient-derived fibroblasts. Clones of iPSCs with c.187T>A variant and those with both variants largely restored their osteogenic capacities after CRISPR/Cas9 gene editing, which corrected the variants. Importantly, correcting c.187T>A variant alone in CRISPR-edited iPSCs was sufficient to alleviate OI phenotypes, as indicated by increased levels of COL1A1, COL1A2, ALP mRNAs, and COL1A1 protein. Our findings suggest that c.187T>A is the dominant variant of cis-double-variant in COL1A1 that led to OI, and PNA interference and CRISPR/Cas9 gene editing may be new therapeutic tools for OI treatment.

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Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9 correction of a dominant cis-double-variant in COL1A1 isolated from a patient with osteogenesis imperfecta increases the osteogenic capacity of induced pluripotent stem cells

Cao

Ren

et al. 2020

Journal of Bone and Mineral Research

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“…Relative gene expression was evaluated using the 2 −ΔΔct method after normalization to the reference gene. 28 All primers are listed in Supplementary Table S1.…”

Section: Methodsmentioning

confidence: 99%

Indoxyl sulfate impairs in vitro erythropoiesis by triggering apoptosis and senescence

Duangchan

Rattanasompattikul

Chitchongyingcharoen

et al. 2022

Exp Biol Med (Maywood)

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Anemia is a major complication in over 50% of chronic kidney disease (CKD) patients. One of the main causes of anemia in CKD is the reduction of erythropoietin (EPO) synthesis from renal tubular cells. Therefore, first-line treatment of CKD is EPO administration; however, EPO unresponsiveness in several patients is frequently found. More undefined causes of anemia in CKD are under interest, especially uremic toxins, which are a group of solutes accumulated in CKD patients. The highly detectable protein-bound uremic toxin, indoxyl sulfate (IS) was investigated for its effects on in vitro erythropoiesis in this study. CD34+ hematopoietic stem cells were isolated from human umbilical cord blood and differentiated toward erythrocyte lineage for 14 days in various concentrations of IS (12.5, 25, 50, and 100 µg/mL). The effects of IS on cell proliferation, differentiation, apoptosis, and senescence were determined. Cell proliferation was investigated by manual cell counting. Cell surface marker expression was analyzed by flow cytometry. Wright’s staining was performed to evaluate cell differentiation capacity. Apoptosis and senescence marker expression was measured using reverse transcription polymerase chain reaction (RT-PCR). TUNEL assay was performed to detect apoptotic DNA fragmentation. Our results demonstrated that IS reduced cell proliferation and impaired erythrocyte differentiation capacity. In addition, this study confirmed the effects of IS on cell apoptosis and senescence during erythropoietic differentiation. Therefore, the promotion of apoptosis and senescence might be one of the possible mechanisms caused by uremic toxin accumulation leading to anemia in CKD patients.

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“…Notably, 4-PBA promoted Atg5 gene expression and cellular autophagy. Unexpectedly, 4-PBA was found to enhance osteogenic gene expression and mineralization while suppressing apoptotic cell and unfolded protein response (UPR) gene expression . This novel treatment approach aims to address the underlying cellular homeostasis, potentially reducing the severity of the OI phenotype.…”

Section: Current and Future Therapy In Oimentioning

confidence: 99%

Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches

Sun,

Li,

Wang

et al. 2024

ACS Pharmacol. Transl. Sci.

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Osteogenesis imperfecta (OI) is an uncommon genetic disorder characterized by shortness of stature, hearing loss, poor bone mass, recurrent fractures, and skeletal abnormalities. Pathogenic variations have been found in over 20 distinct genes that are involved in the pathophysiology of OI, contributing to the disorder's clinical and genetic variability. Although medications, surgical procedures, and other interventions can partially alleviate certain symptoms, there is still no known cure for OI. In this Review, we provide a comprehensive overview of genetic pathogenesis, existing treatment modalities, and new developments in biotechnologies such as gene editing, stem cell reprogramming, functional differentiation, and transplantation for potential future OI therapy.

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Amelioration of osteogenesis in iPSC-derived mesenchymal stem cells from osteogenesis imperfecta patients by endoplasmic reticulum stress inhibitor

Cited by 16 publications

References 81 publications

CRISPR/Cas9 correction of a dominant cis-double-variant in COL1A1 isolated from a patient with osteogenesis imperfecta increases the osteogenic capacity of induced pluripotent stem cells

CRISPR/Cas9 correction of a dominant cis-double-variant in COL1A1 isolated from a patient with osteogenesis imperfecta increases the osteogenic capacity of induced pluripotent stem cells

Indoxyl sulfate impairs in vitro erythropoiesis by triggering apoptosis and senescence

Emerging Landscape of Osteogenesis Imperfecta Pathogenesis and Therapeutic Approaches

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