Activation of Neural Cell Fate Programs Toward Direct Conversion of Adult Human Fibroblasts into Tri-Potent Neural Progenitors Using <i>OCT-4</i>

Mitchell, Ryan R.; Szabó, Éva; Benoit, Yannick D.; Case, Daniel T.; Mechael, Rami; Alamilla, Javier; Lee, Jong Hee; Fiebig‐Comyn, Aline; Gillespie, Deda C.; Bhatia, Mickie

doi:10.1089/scd.2014.0023

Cited by 65 publications

(82 citation statements)

References 24 publications

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“…Recent cell reprogramming protocols describe the direct conversion of human fibroblasts to "induced" neural stem cells, able to further differentiate into the three CNS lineages (neurons, astrocytes and oligodendrocytes) following appropriate culture conditions. Artificial and temporal expression of specific transcription factors such as Oct-3/4, Sox2, Klf4, Brn4 and c-myc seems to govern the cell conversion towards a neural fate [76][77][78] . Molecular pathways and key transcription factors making transdifferentiation possible are currently under investigation for different cell types [79] .…”

Section: In Vivo or In Vitro Transdifferentiationmentioning

confidence: 99%

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Nicaise

Mitrečić

Falnikar

et al. 2015

WJSC

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in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology. Core tip: Amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI) result in incurable neurological dysfunction due to loss of spinal motor neurons and axonal degeneration, amongst other mechanisms. Astrocytes are increasingly recognized as being necessary for neuroprotection and regeneration in the central nervous system as they promote axonal growth and deliver essential neurotrophic factors under both physiological and pathophysiological conditions. Given the central role played by astrocytes, we gathered convincing results from ALS and SCI literature that argue in favor of stem cell-based astrocyte replacement therapies and stress the scientific community to investigate more deeply the molecular understanding of astrocyte biology. MULTIPLE FACETS OF ASTROCYTES IN THE CENTRAL NERVOUS SYSTEM Astrocyte functionsAstrocytes are the most abundant cells in the central nervous system (CNS), outnumbering neuronal cells by several fold in some CNS regions. They have long been relegated to a secondary position, behind neurons or oligodendrocytes, as many thought that astrocytes were barely by-standers of the CNS. Accounting for a large fraction of the brain volume, their particular shape and tissue distribution are known to elaborate an extensive network of fine interconnected processes. Their star-shaped morphology projecting long branched processes provides a large coverage of CNS structures and the ensheathment of the brain or spinal cord in the pia matter. They draw the whole brain microanatomy by secreting astrocyte-derived extracellular matrix proteins (e.g., chondroitin sulfate proteoglycans, hyaluronan, tenascin proteins family, thrombospondin), thereby providing structural support for nervous system cells. Beside their structural role, astrocytes are recognized to fulfill and support many, if not all, functions of the healthy CNS [1] . Astrocyte endfeet cover more than 90% of the CNS vasculature and come in contact with endothelial cells. Expressing key glucose transporter-1, astrocytes convoy glucose from blood vessels to nervous system cells, most of them being devoid of direct access to this high-end source of energy. Hence, astrocytes synthetize via specific metabolic pathways glycogen and lactate, main energy fuels for neurons or distant synapses. Through humoral factors released at the perivascular space, astrocytes control local cerebral blood flow and bloodbrain barrier (BBB) integrity. Transforming growth factor-beta, glial-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2) and angiopoietin 1 (binding the endothelium-specific receptor TIE2), all secreted at the vascular end-feet, act on endothelial cells in order to induce or maintain an operational BBB [2,3] . Astrocytes-released growth factors [e.g., brainderived neurotrophic factor, BDNF; ciliary neurotrophic factor (CNTF)] exert beneficial effects far beyond the perivascular spa...

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Section: In Vivo or In Vitro Transdifferentiationmentioning

confidence: 99%

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Nicaise

Mitrečić

Falnikar

et al. 2015

WJSC

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“…Overexpression of the four Yamanaka factors in fibroblasts was shown to generate a source of proliferating neutrally committed cells through direct conversion by destabilizing the somatic cells into a pre-iPSC stage 128,129 . This paradigm has been utilized in both mouse and human fibroblasts.…”

Section: Direct Conversion To Neural Cellsmentioning

confidence: 99%

Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience

et al. 2016

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The scarcity of live human brain cells for experimental access has for a long time limited our ability to study complex human neurological disorders and elucidate basic neuroscientific mechanisms. A decade ago, the development of methods to reprogramme somatic human cells into induced pluripotent stem cells enabled the in vitro generation of a wide range of neural cells from virtually any human individual. The growth of methods to generate more robust and defined neural cell types through reprogramming and direct conversion into induced neurons has led to the establishment of various human reprogramming-based neural disease models.

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“…Other approaches involve overexpression of lineagespecific transcription factors, with examples of induced cells generated using individual factors, such as Oct4 [121] , Sox2 [122] , Sox10 [103] , and Nanog [110] , as well as different sets of factors [111,123] . Additionally, a number of studies have also incorporated the use of small molecules such as TGF-β [118] , GSK-3 [119] , MEK [112] , ROCK [112] , BMP [112] , JAK [109] , and histone deacetylase [103,120] inhibitors to enhance direct conversion.…”

Section: Generation Of Induced Neural Stem and Progenitor Cellsmentioning

confidence: 99%

Generation of diverse neural cell types through direct conversion

Petersen

Strappe

2016

WJSC

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Activation of Neural Cell Fate Programs Toward Direct Conversion of Adult Human Fibroblasts into Tri-Potent Neural Progenitors Using OCT-4

Cited by 65 publications

References 24 publications

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Evaluating cell reprogramming, differentiation and conversion technologies in neuroscience

Generation of diverse neural cell types through direct conversion

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