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1.
Neuron ; 112(7): 1035-1037, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38574725

RESUMO

Direct conversion of non-neuronal cells to neurons offers opportunities for disease modeling and therapy. In this issue of Neuron, Sonsalla et al.1 reveal the unfolded protein response (UPR) pathway as a "proteomic roadblock" to direct neuronal conversion; overcoming this roadblock enhances reprogramming.


Assuntos
Neurônios , Proteômica , Neurônios/metabolismo , Resposta a Proteínas não Dobradas
2.
Nat Commun ; 15(1): 1816, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38418829

RESUMO

The design of human model systems is highly relevant to unveil the underlying mechanisms of aging and to provide insights on potential interventions to extend human health and life span. In this perspective, we explore the potential of 2D or 3D culture models comprising human induced pluripotent stem cells and transdifferentiated cells obtained from aged or age-related disorder-affected donors to enhance our understanding of human aging and to catalyze the discovery of anti-aging interventions.


Assuntos
Células-Tronco Pluripotentes Induzidas , Humanos , Idoso , Envelhecimento , Reprogramação Celular/genética , Longevidade
3.
Cell Reprogram ; 24(5): 304-313, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35877103

RESUMO

The direct conversion of adult human skin fibroblasts (FBs) into induced neurons (iNs) represents a useful technology to generate donor-specific adult-like human neurons. Disease modeling studies rely on the consistently efficient conversion of relatively large cohorts of FBs. Despite the identification of several small molecular enhancers, high-yield protocols still demand addition of recombinant Noggin. To identify a replacement to circumvent the technical and economic challenges associated with Noggin, we assessed dynamic gene expression trajectories of transforming growth factor-ß signaling during FB-to-iN conversion. We identified ALK2 (ACVR1) of the bone morphogenic protein branch to possess the highest initial transcript abundance in FBs and the steepest decline during successful neuronal conversion. We thus assessed the efficacy of dorsomorphin homolog 1 (DMH1), a highly selective ALK2-inhibitor, for its potential to replace Noggin. Conversion media containing DMH1 (+DMH1) indeed enhanced conversion efficiencies over basic SMAD inhibition (tSMADi), yielding similar ßIII-tubulin (TUBB3) purities as conversion media containing Noggin (+Noggin). Furthermore, +DMH1 induced high yields of iNs with clear neuronal morphologies that are positive for the mature neuronal marker NeuN. Validation of +DMH1 for iN conversion of FBs from 15 adult human donors further demonstrates that Noggin-free conversion consistently yields iN cultures that display high ßIII-tubulin numbers with synaptic structures and basic spontaneous neuronal activity at a third of the cost.


Assuntos
Neurônios , Pirazóis , Pirimidinas , Tubulina (Proteína) , Proteínas de Transporte , Humanos , Neurônios/citologia , Fatores de Crescimento Transformadores/metabolismo , Tubulina (Proteína)/metabolismo
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