Reprogramming of Pericyte-Derived Cells of the Adult Human Brain into Induced Neuronal Cells
ABSTRACT Reprogramming of somatic cells into neurons provides a new approach toward cell-based therapy of neurodegenerative diseases. A major challenge for the translation of neuronal reprogramming into therapy is whether the adult human brain contains cell populations amenable to direct somatic cell conversion. Here we show that cells from the adult human cerebral cortex expressing pericyte hallmarks can be reprogrammed into neuronal cells by retrovirus-mediated coexpression of the transcription factors Sox2 and Mash1. These induced neuronal cells acquire the ability of repetitive action potential firing and serve as synaptic targets for other neurons, indicating their capability of integrating into neural networks. Genetic fate-mapping in mice expressing an inducible Cre recombinase under the tissue-nonspecific alkaline phosphatase promoter corroborated the pericytic origin of the reprogrammed cells. Our results raise the possibility of functional conversion of endogenous cells in the adult human brain to induced neuronal fates.
- SourceAvailable from: Terry C Burns
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- "Overexpression of key transcription factors such as Neurogenein2, Mash1 or Sox2 can convert pericytes, astroglia or oligodendrocyte progenitor cells into functional neurons in situ (Heinrich et al., 2014; Heinrich et al., 2010; Karow et al., 2012). Such exciting technologies offer unprecedented potential to fundamentally reconfigure the structure and function of diseased brain regions. "
ABSTRACT: Decisions about what experimental therapies are advanced to clinical trials are based almost exclusively on findings in preclinical animal studies. Over the past 30 years, animal models have forecast the success of hundreds of neuroprotective pharmacological therapies for stroke, Alzheimer׳s disease, spinal cord injury, traumatic brain injury and amyotrophic lateral sclerosis. Yet almost without exception, all have failed. Rapid advances in stem cell technologies have raised new hopes that these neurological diseases may one day be treatable. Still, how can neuroregenerative therapies be translated into clinical realities if available animal models are such poor surrogates of human disease? To address this question we discuss human and rodent neurogenesis, evaluate mechanisms of action for cellular therapies and describe progress in translating neuroregeneration to date. We conclude that not only are appropriate animal models critical to the development of safe and effective therapies, but that the multiple mechanisms of stem cell-mediated therapies may be particularly well suited to the mechanistically diverse nature of central nervous system diseases in mice and man. Copyright © 2015. Published by Elsevier B.V.European journal of pharmacology 03/2015; 759. DOI:10.1016/j.ejphar.2015.03.041 · 2.68 Impact Factor
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- "In this context, studies have defined sets of transcription factors that can directly reprogram somatic cells into another cell type without passing through the pluripotent state (Ginsberg et al., 2012; Ieda et al., 2010; Karow et al., 2012; Vierbuchen et al., 2010). Using a strategy of re-expressing key developmental regulators in vitro/in vivo, adult cell reprogramming occurs, through which induced cells residing in their native environment might promote their survival and/or maturation (Ginsberg et al., 2012; Ieda et al., 2010; Karow et al., 2012; Qian et al., 2012; Vierbuchen et al., 2010; Zhou et al., 2008). "
ABSTRACT: The application of cell-based therapies in regenerative medicine is gaining recognition. Here, we show that human bone marrow stromal cells (BMSCs), also known as bone-marrow-derived mesenchymal cells, can be reprogrammed into renal proximal tubular-like epithelial cells using cell-free extracts. Streptolysin-O-permeabilized BMSCs exposed to HK2-cell extracts underwent morphological changes-formation of "domes" and tubule-like structures-and acquired epithelial functional properties such as transepithelial-resistance, albumin-binding, and uptake and specific markers E-cadherin and aquaporin-1. Transmission electron microscopy revealed the presence of brush border microvilli and tight intercellular contacts. RNA sequencing showed tubular epithelial transcript abundance and revealed the upregulation of components of the EGFR pathway. Reprogrammed BMSCs integrated into self-forming kidney tissue and formed tubular structures. Reprogrammed BMSCs infused in immunodeficient mice with cisplatin-induced acute kidney injury engrafted into proximal tubuli, reduced renal injury and improved function. Thus, reprogrammed BMSCs are a promising cell resource for future cell therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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- "A growing number of studies report successful direct neural conversion from various somatic cells and from stem cells to functional neurons (Caiazzo et al., 2011; Karow et al., 2012; Pang et al., 2011; Pfisterer et al., 2011a; Son et al., 2011; Vierbuchen et al., 2010; Zhang et al., 2013) and also direct conversion of somatic cells into a variety of mature, clinically relevant cell types such as oligodendrocytes, cardiomyocytes, and hepatocytes (Ieda et al., 2010; Sekiya and Suzuki, 2011; Yang et al., 2013). Because direct conversion does not involve a stem cell intermediate , it has some clear benefits when it comes to developing the cells for clinical use. "
ABSTRACT: Recent findings show that human fibroblasts can be directly programmed into functional neurons without passing via a proliferative stem cell intermediate. These findings open up the possibility of generating subtype-specific neurons of human origin for therapeutic use from fetal cell, from patients themselves, or from matched donors. In this study, we present an improved system for direct neural conversion of human fibroblasts. The neural reprogramming genes are regulated by the neuron-specific microRNA, miR-124, such that each cell turns off expression of the reprogramming genes once the cell has reached a stable neuronal fate. The regulated system can be combined with integrase-deficient vectors, providing a nonintegrative and self-regulated conversion system that rids problems associated with the integration of viral transgenes into the host genome. These modifications make the system suitable for clinical use and therefore represent a major step forward in the development of induced neurons for cell therapy. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.Cell Reports 12/2014; 9(5). DOI:10.1016/j.celrep.2014.11.017 · 8.36 Impact Factor