Directed differentiation of functional astroglial subtypes from human pluripotent stem cells

Krencik, Robert; Zhang, Su‐Chun

doi:10.1038/nprot.2011.405

Cited by 221 publications

(191 citation statements)

References 29 publications

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…The differentiation of NI NPCs into astrocytes was promoted by a standardized protocol (Krencik and Zhang, 2011) with slight modifications. In brief, NPCs were cultured as neurospheres in uncoated flasks with NI medium for 3 months during which progenitor clusters switched from neurogenic neurospheres to gliogenic astrospheres.…”

Section: Generation Of Ni Npcsmentioning

confidence: 99%

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

et al. 2017

View full text Add to dashboard Cite

SUMMARYMitochondrial DNA (mtDNA) mutations frequently cause neurological diseases. Modeling of these defects has been difficult because of the challenges associated with engineering mtDNA. We show here that neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) retain the parental mtDNA profile and exhibit a metabolic switch toward oxidative phosphorylation. NPCs derived in this way from patients carrying a deleterious homoplasmic mutation in the mitochondrial gene MT-ATP6 (m.9185T>C) showed defective ATP production and abnormally high mitochondrial membrane potential (MMP), plus altered calcium homeostasis, which represents a potential cause of neural impairment. High-content screening of FDA-approved drugs using the MMP phenotype highlighted avanafil, which we found was able to partially rescue the calcium defect in patient NPCs and differentiated neurons. Overall, our results show that iPSC-derived NPCs provide an effective model for drug screening to target mtDNA disorders that affect the nervous system.

show abstract

Section: Generation Of Ni Npcsmentioning

confidence: 99%

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

et al. 2017

View full text Add to dashboard Cite

show abstract

“…These cells can be used to model human pathological processes in vitro and in vivo as well as for therapeutic transplantation [163] . More recently the Zhang laboratory reported another shorter duration protocol for generating astrocytes from iPSCs by differentiation of these cells into neuroepithelial cells, followed by removal of mitogen and treatment with CNTF to induce differentiation into astrocytes [70] . Recently, the Maragakis lab conducted transplantation of iPSC-and ESC-derived immature astrocytes into rodent spinal cord.…”

Section: Lessons From Transplantation Paradigms In Sci Modelsmentioning

confidence: 99%

“…Astrocytes generated by this protocol were characterized by specific gene expression profiles, neurotransmitter and ionic uptake, support of neuronal maturation, and importantly expression of specific sets of homeodomain transcription factors that specify functional identity [69] . On the basis of this, another protocol was recently reported for an efficient generation of immature astrocytes from human pluripotent stem cells (hPSCs) [70] . The protocol consists of three steps.…”

Section: Embryonic or Induced-pluripotent Stem Cellsmentioning

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

View full text Add to dashboard Cite

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...

show abstract

“…In recent years investigators have developed methods to derive and maintain astrocytes from patient iPSCs (261)(262)(263). The question as to whether these cells truly represent functioning astrocytes in aged human brains remains to be answered (264).…”

Section: Future Perspectivesmentioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

View full text Add to dashboard Cite

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

show abstract

Directed differentiation of functional astroglial subtypes from human pluripotent stem cells

Cited by 221 publications

References 29 publications

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

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

Astrocytic transporters in Alzheimer's disease

Contact Info

Product

Resources

About