The Use of Fibroblasts from Patients with Inherited Mitochondrial Disorders for Pathomechanistic Studies and Evaluation of Therapies

Soiferman, Devorah; Saada, Ann

doi:10.1002/9781119017127.ch18

Cited by 2 publications

(4 citation statements)

References 106 publications

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“…29 Healthy ICO data were compared to whole liver and fibroblasts, the latter of which is the most commonly used in vitro model for IEMs. 1,[30][31][32][33] We found a great variety in ICO IEM gene expression, confirming our previous notion that ICOs are a suitable in vitro model for a specific selection of metabolic categories (Figures 3 and S2A-B). Interestingly, this variation was also observed within each metabolic category of ICOs and fibroblasts.…”

Section: Expression Of Genes Involved In Iemssupporting

confidence: 87%

“…Bulk RNA sequencing (RNAseq) was analyzed for IEM expression using the Radboudumc Exome panel for metabolic disorders 29 . Healthy ICO data were compared to whole liver and fibroblasts, the latter of which is the most commonly used in vitro model for IEMs 1,30–33 …”

Section: Resultsmentioning

confidence: 99%

“…29 Healthy ICO data were compared to whole liver and fibroblasts, the latter of which is the most commonly used in vitro model for IEMs. 1 , 30 , 31 , 32 , 33 …”

Section: Resultsmentioning

confidence: 99%

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The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

Lehmann

Schene

Ardisasmita

et al. 2021

J of Inher Metab Disea

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Inborn errors of metabolism (IEMs) comprise a diverse group of individually rare monogenic disorders that affect metabolic pathways. Mutations lead to enzymatic deficiency or dysfunction, which results in intermediate metabolite accumulation or deficit leading to disease phenotypes. Currently, treatment options for many IEMs are insufficient. Rarity of individual IEMs hampers therapy development and phenotypic and genetic heterogeneity suggest beneficial effects of personalized approaches. Recently, cultures of patient-own liverderived intrahepatic cholangiocyte organoids (ICOs) have been established. Since most metabolic genes are expressed in the liver, patient-derived ICOs represent exciting possibilities for in vitro modeling and personalized drug testing for IEMs. However, the exact application range of ICOs remains unclear.To address this, we examined which metabolic pathways can be studied with ICOs and what the potential and limitations of patient-derived ICOs are to model metabolic functions. We present functional assays in patient ICOs with defects in branched-chain amino acid metabolism (methylmalonic acidemia), Bart Spee and Sabine A. Fuchs authors contributed equally to this work. Sabine A. Fuchs: On behalf of United for Metabolic Diseases (UMD).

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Section: Expression Of Genes Involved In Iemssupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

Lehmann

Schene

Ardisasmita

et al. 2021

J of Inher Metab Disea

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show abstract

“…The use of patient skin-derived fibroblasts has been widely utilized to model numerous diseases of metabolic, neurodegenerative, and lysosomal origin (Solini et al, 2004; McNeill et al, 2014; Alvarez-Mora et al, 2017; Konrad et al, 2017). For mitochondrial diseases, fibroblasts constitute the model of choice to diagnose and often to support research of these entities (Cameron et al, 2004; Soiferman and Saada, 2015; Ferrer-Cortès et al, 2016). Several studies in PD have used human skin-derived fibroblasts to investigate the molecular mechanisms underlying disease etiopathogenesis (Auburger et al, 2012).…”

Section: Models To Study Parkinson’s Diseasementioning

confidence: 99%

Bioenergetics and Autophagic Imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration

et al. 2019

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder worldwide affecting 2–3% of the population over 65 years. This prevalence is expected to rise as life expectancy increases and diagnostic and therapeutic protocols improve. PD encompasses a multitude of clinical, genetic, and molecular forms of the disease. Even though the mechanistic of the events leading to neurodegeneration remain largely unknown, some molecular hallmarks have been repeatedly reported in most patients and models of the disease. Neuroinflammation, protein misfolding, disrupted endoplasmic reticulum-mitochondria crosstalk, mitochondrial dysfunction and consequent bioenergetic failure, oxidative stress and autophagy deregulation, are amongst the most commonly described. Supporting these findings, numerous familial forms of PD are caused by mutations in genes that are crucial for mitochondrial and autophagy proper functioning. For instance, late and early onset PD associated to mutations in Leucine-rich repeat kinase 2 (LRRK2) and Parkin (PRKN) genes, responsible for the most frequent dominant and recessive inherited forms of PD, respectively, have emerged as promising examples of disease due to their established role in commanding bioenergetic and autophagic balance. Concomitantly, the development of animal and cell models to investigate the etiology of the disease, potential biomarkers and therapeutic approaches are being explored. One of the emerging approaches in this context is the use of patient’s derived cells models, such as skin-derived fibroblasts that preserve the genetic background and some environmental cues of the patients. An increasing number of reports in these PD cell models postulate that deficient mitochondrial function and impaired autophagic flux may be determinant in PD accelerated nigral cell death in terms of limitation of cell energy supply and accumulation of obsolete and/or unfolded proteins or dysfunctional organelles. The reliance of neurons on mitochondrial oxidative metabolism and their post-mitotic nature, may explain their increased vulnerability to undergo degeneration upon mitochondrial challenges or autophagic insults. In this scenario, proper mitochondrial function and turnover through mitophagy, are gaining in strength as protective targets to prevent neurodegeneration, together with the use of patient-derived fibroblasts to further explore these events. These findings point out the presence of molecular damage beyond the central nervous system (CNS) and proffer patient-derived cell platforms to the clinical and scientific community, which enable the study of disease etiopathogenesis and therapeutic approaches focused on modifying the natural history of PD through, among others, the enhancement of mitochondrial function and autophagy.

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The Use of Fibroblasts from Patients with Inherited Mitochondrial Disorders for Pathomechanistic Studies and Evaluation of Therapies

Cited by 2 publications

References 106 publications

The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

The potential and limitations of intrahepatic cholangiocyte organoids to study inborn errors of metabolism

Bioenergetics and Autophagic Imbalance in Patients-Derived Cell Models of Parkinson Disease Supports Systemic Dysfunction in Neurodegeneration

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