A roadmap for neurodevelopmental disease modeling for non-stem cell biologists

Ernst, Carl

doi:10.1002/sctm.19-0344

Cited by 5 publications

(6 citation statements)

References 63 publications

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“…suggest that SETBP1 SGS mutations lead to SETBP1 accumulation in neurons and increased DNA damage which might suggest that association with SET and DNA nuclease activity may be important ( Banfi et al, 2021 ). With the ability to rapidly make mouse models via CRISPR and to model human derived somatic cells from SGS/SDD cases in a neuronal context ( Ernst, 2020 ), we expect rapid advances in the underlying mechanism of these two disorders. Both SGS and SDD mutation will lend themselves well to iPSC tissue modeling as monogenic diseases.…”

Section: Future Considerationsmentioning

confidence: 99%

Putative Roles of SETBP1 Dosage on the SET Oncogene to Affect Brain Development

Antonyan

Ernst

2022

Front. Neurosci.

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Mutations in SET BINDING PROTEIN 1 (SETBP1) cause two different clinically distinguishable diseases called Schinzel–Giedion syndrome (SGS) or SETBP1 deficiency syndrome (SDD). Both disorders are disorders of protein dosage, where SGS is caused by decreased rate of protein breakdown due to mutations in a proteosome targeting domain, and SDD is caused by heterozygous loss-of-function mutations leading to haploinsufficiency. While phenotypes of affected individuals support a role for SETBP1 in brain development, little is known about the mechanisms that might underlie this. The binding partner which gave SETBP1 its name is SET and there is extensive literature on this important oncogene in non-neural tissues. Here we describe different molecular complexes in which SET is involved as well as the role of these complexes in brain development. Based on this information, we postulate how SETBP1 protein dosage might influence these SET-containing molecular pathways and affect brain development. We examine the roles of SET and SETBP1 in acetylation inhibition, phosphatase activity, DNA repair, and cell cycle control. This work provides testable hypotheses for how altered SETBP1 protein dosage affects brain development.

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Section: Future Considerationsmentioning

confidence: 99%

Putative Roles of SETBP1 Dosage on the SET Oncogene to Affect Brain Development

Antonyan

Ernst

2022

Front. Neurosci.

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“…As these urinederived stem cells (UDSCs) can be isolated non-invasively at low costs and reprogram efficiently (Zhou et al, 2012), they are increasingly used to generate iPSCs from patients (e.g. (Ernst, 2020;Gaignerie et al, 2018;Xue et al, 2013). Perhaps the only major drawback of using UDSCs for iPSC generation is that the number of UDSCs per millilitre is quite variable within and among individualsEven when collecting large volumes, isolation can fail as we also see in our study (Table S1).…”

Section: Implications For Using Urine For Generating Human Ipscsmentioning

confidence: 99%

A non-invasive method to generate induced pluripotent stem cells from primate urine

Geuder

Ohnuki

Wange

et al. 2020

Preprint

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SummaryComparing the molecular and cellular properties among primates is crucial to better understand human evolution and biology. However, it is difficult or ethically even impossible to collect matched tissues from many primates, especially during development. An alternative is to model different cell types and their development using induced pluripotent stem cells (iPSCs). These can be generated from many tissue sources, but non-invasive sampling would decisively broaden the spectrum of non-human primates that can be investigated. Here, we report the generation of primate iPSCs from urine samples. We first validate and optimize the procedure using human urine samples and show that Sendai virus transduction of reprogramming factors into urinary cells efficiently generates integration-free iPSCs, which maintain their pluripotency under feeder-free culture conditions. We demonstrate that this method is also applicable to gorilla and orangutan urinary cells isolated from a non-sterile zoo floor. We characterize the urinary cells, iPSCs and derived neural progenitor cells using karyotyping, immunohistochemistry, differentiation assays and RNA-sequencing. We show that the urine-derived human iPSCs are indistinguishable from well characterized PBMC-derived human iPSCs and that the gorilla and orangutan iPSCs are well comparable to the human iPSCs. In summary, this study introduces a novel and efficient approach to generate iPSCs non-invasively from primate urine. This will allow to extend the zoo of species available for a comparative approach to molecular and cellular phenotypes.Graphical AbstractWorkflow overview for establishing iPSCs from primate urine(A) We established the protocol for human urine based on a previous description (Zhou 2012). We tested volume, storage and culture conditions for primary cells and compared reprogramming by overexpression of OCT3/4, SOX2, KLF4 and MYC (OSKM) via lipofection of episomal vectors and via transduction of a sendai virus derived vector (SeV). (B) We used the the protocol established in humans and adapted it for unsterile floor-collected samples from non-human primates by adding Normocure to the first passages of primary cell culture and reprogrammed visually healthy and uncontaminated cultures using SeV. (C) Pluripotency of established cultures was verified by marker expression, differentiation capacity and cell type classification using RNA sequencing.

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“…As these urine-derived stem cells (UDSCs) can be isolated non-invasively at low costs and reprogrammed efficiently 16 , they are increasingly used to generate iPSCs from patients (e.g. [33][34][35] ). Perhaps the only major drawback of using UDSCs for iPSC generation is that the number of UDSCs that can be grown per milliliter is quite variable among samples.…”

Section: Discussionmentioning

confidence: 99%

A non-invasive method to generate induced pluripotent stem cells from primate urine

Geuder

Wange

Janjic

et al. 2021

Sci Rep

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Comparing the molecular and cellular properties among primates is crucial to better understand human evolution and biology. However, it is difficult or ethically impossible to collect matched tissues from many primates, especially during development. An alternative is to model different cell types and their development using induced pluripotent stem cells (iPSCs). These can be generated from many tissue sources, but non-invasive sampling would decisively broaden the spectrum of non-human primates that can be investigated. Here, we report the generation of primate iPSCs from urine samples. We first validate and optimize the procedure using human urine samples and show that suspension- Sendai Virus transduction of reprogramming factors into urinary cells efficiently generates integration-free iPSCs, which maintain their pluripotency under feeder-free culture conditions. We demonstrate that this method is also applicable to gorilla and orangutan urinary cells isolated from a non-sterile zoo floor. We characterize the urinary cells, iPSCs and derived neural progenitor cells using karyotyping, immunohistochemistry, differentiation assays and RNA-sequencing. We show that the urine-derived human iPSCs are indistinguishable from well characterized PBMC-derived human iPSCs and that the gorilla and orangutan iPSCs are well comparable to the human iPSCs. In summary, this study introduces a novel and efficient approach to non-invasively generate iPSCs from primate urine. This will extend the zoo of species available for a comparative approach to molecular and cellular phenotypes.

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A roadmap for neurodevelopmental disease modeling for non-stem cell biologists

Cited by 5 publications

References 63 publications

Putative Roles of SETBP1 Dosage on the SET Oncogene to Affect Brain Development

Putative Roles of SETBP1 Dosage on the SET Oncogene to Affect Brain Development

A non-invasive method to generate induced pluripotent stem cells from primate urine

A non-invasive method to generate induced pluripotent stem cells from primate urine

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