hESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury

Jiang, Peng; Chen, Chen; Wang, Ruimin; Chechneva, Olga; Chung, Siu-Leung; Rao, Mahendra S.; Pleasure, David E; Liu, Ying; Zhang, Quanguang; Deng, Wenbin

doi:10.1038/ncomms3196

Cited by 75 publications

(120 citation statements)

References 54 publications

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“…Human PSCs include embryonic stem cells (ESCs) and induced pluripotent stem cells (IPSCs) which often are the primary source of material used to study neuronal subtypes in vitro using protocols M A N U S C R I P T ACCEPTED MANUSCRIPT 5 that include time-specific exposure to patterning cues following developmental principles (Hu et al, 2010;Swistowski et al, 2010). Recently, different protocols have also been described for the differentiation of human PSCs into regionalized astrocytes in vitro (Jiang et al, 2013;Juopperi et al, 2012;Kondo et al, 2013;Krencik et al, 2011;Roybon et al, 2013;Serio et al, 2013;Shaltouki et al, 2013;Yuan et al, 2011). However, as opposed to the multitude developed for generating spinal cord astrocytes (Jiang et al, 2013;Krencik et al, 2011;Roybon et al, 2013;Serio et al, 2013), only few exist for generating forebrain and midbrain astrocytes (Juopperi et al, 2012;Kondo et al, 2013;Krencik et al, 2011).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Recently, different protocols have also been described for the differentiation of human PSCs into regionalized astrocytes in vitro (Jiang et al, 2013;Juopperi et al, 2012;Kondo et al, 2013;Krencik et al, 2011;Roybon et al, 2013;Serio et al, 2013;Shaltouki et al, 2013;Yuan et al, 2011). However, as opposed to the multitude developed for generating spinal cord astrocytes (Jiang et al, 2013;Krencik et al, 2011;Roybon et al, 2013;Serio et al, 2013), only few exist for generating forebrain and midbrain astrocytes (Juopperi et al, 2012;Kondo et al, 2013;Krencik et al, 2011). The efficiency of these protocols to generate astrocytes, however, varies greatly not only depending on the type of PSCs primarily used, but also in-between individual iPSC lines generated from one or multiple patients.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Generation of human pluripotent stem cell reporter lines for the isolation of and reporting on astrocytes generated from ventral midbrain and ventral spinal cord neural progenitors

et al. 2015

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Astrocytes play a critical role during the development and the maintenance of the CNS in health and disease. Yet, their lack of accessibility from fetuses and from the brain of diseased patients has hindered our understanding of their full implication in developmental and pathogenic processes. Human pluripotent stem cells (PSCs) are an alternative source to obtain large quantities of astrocytes in vitro, for mechanistic studies of development and disease. However, these studies often require highly pure populations of astrocytes, which are not always achieved, depending on the PSC lines and protocols used. Here, we describe the generation and characterization of human PSC reporter lines expressing TagRFP driven by the ABC1D region of the human GFAP promoter, as new cellular model for generating homogenous population of astrocytes generated from CNS regionally defined PSC-derived neural progenitors. GFA(ABC1D)::TagRFP-expressing astrocytes can be purified by fluorescent-activated cell sorting and maintain a bright expression for several additional weeks. These express canonical astrocyte markers NF1A, S100β, CX43, GLAST, GS and CD44. These new cellular models, from which highly pure populations of fluorescence-expressing astrocytes can be obtained, provide a new platform for studies where pure or fluorescently labeled astrocyte populations are necessary, for example to assess pro-inflammatory cytokine and chemokine release in response to specific treatment, and uptake and degradation of fluorescently labeled pathogenic proteins, as reported in this study.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

Generation of human pluripotent stem cell reporter lines for the isolation of and reporting on astrocytes generated from ventral midbrain and ventral spinal cord neural progenitors

et al. 2015

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“…2 The major aim for development of hESCs was to use these cells for regenerative medicine because of their potential to proliferate and differentiate into any cell type of the human body, such as brain cells (neurons, astrocytes, glial cells, etc), blood cells (erythrocytes, lymphocytes, etc), liver cells, cardiac muscle cells, pancreatic cells, and skin cells. [3][4][5][6][7][8] This potential has led to its widespread application in the fields of human developmental biology, drug discovery, drug testing, and tissue engineering and transplant medicine. [9][10][11] Furthermore, the differentiated derivatives of hESCs could be used for (1) identification of gene targets for new drugs, (2) testing the toxicity or teratogenicity of new compounds, and (3) transplant to replace cells destroyed by disease.…”

Section: Introductionmentioning

confidence: 99%

Untitled

Shroff¹,

Vatsa²

2017

Exp Clin Transplant

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Objectives: Human embryonic stem cells are pluripotent cell lines usually derived from human blastocysts. Their potential critically depends on longterm proliferative capacity, developmental potential after prolonged culture, and karyotypic stability. Cell viability is an important parameter for assessing cell sample quality. Here, we elaborate the stored human embryonic stem cell lines' viability in a ready to use form for a period of 9 years (from 2007 to 2015). Materials and Methods: Spare pre implantation stage in vitro fertilized ovum-derived cell lines were cultured in suitable media. Thereafter, they were centrifuged at 1000 revolutions/min over 5 minutes, and pellets were suspended in normal saline. Next, they were tested for viability from storage at -20°C. After being allowed to thaw slowly, the cells were stained with propidium iodide and analyzed using flow cytometry. Images of cells were taken at ×40 and ×100 magnification. Results: At ×100 magnification, cell population size ranged from 0.2 to 2 µm. The percentage of live cells was more than 95% throughout the 9 years. Cells frozen in 2015 showed cell viability of 96.8%. Conclusions: We observed high cell viability in our cell lines for 9 years. Human embryonic stem cell lines in a ready-to-use form can be preserved for longterm purposes. Thus, they could be made available globally.

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“…10 However, to achieve optimal outcome, defined protocols need to be developed for generating human astroglial cells ideally suitable for cellular transplants. 4,11 We believe that the human iPSC technology, combined with newly discovered information about the developing brain may be applied to patients and change the standard of care for children at risk for developmental disabilities and neurological problems.…”

Section: Introductionmentioning

confidence: 99%

“…Human astrocytes are much bigger in size and much more complex in both structure and function than rodent astrocytes. 12,13 Our recent studies 5,11 are thus aimed to develop stem cell derived human astroglial transplants for therapy. We present data showing that immature human iPSCderived astroglial transplants are highly protective against hypoxic-ischemic white matter injury and improve functional outcome.…”

Section: Introductionmentioning

confidence: 99%

Regenerating white matter using human iPSC-derived immature astroglia

Jiang

Deng

2016

Neurogenesis

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Astrocytes traditionally were thought to have merely a support function, but are now understood to be important regulators of neural development and function. The immature and mature astrocytes have stage-specific roles in neuronal development. However, it is largely unclear whether human astrocytes also serve stage-specific roles in oligodendroglial development. Owing to the broad and diverse roles of astroglia in the central nervous system, transplantation of astroglia also could be of therapeutic value in promoting regeneration after CNS injury or disease. Our recent study (Jiang et al., 2016) explores the developmental interactions between astroglia and oligodendroglia, using a human induced pluripotent stem cell (hiPSC) model. By generating immature and mature human astrocytes from hiPSCs, we reveal previously unrecognized effects of immature human astrocytes on oligodendrocyte development. Notably, tissue inhibitor of metalloproteinase-1 (TIMP-1) is differentially expressed in the immature and mature human astrocytes, and mediates at least in part the effects of immature human astrocytes on oligodendroglial differentiation. Furthermore, we demonstrate that hiPSC-derived astroglial transplants promote cerebral white matter regeneration and behavioral recovery in a neonatal mouse model of hypoxic-ischemic injury. Our study provides novel insights into the astro-oligodendroglial cell interaction and has important implications for possible therapeutic interventions for human white matter diseases. Astrocytes are critical players in organizing and maintaining brain structure and function.1 Recent studies discover that astrocytes served stage-specific roles in assisting neuronal development, such as synapse stabilization and elimination. 2,3 In our recent studies, we asked whether astrocytes, at specific immature and mature stages, differently regulate the development of oligodendrocytes, myelin-producing cells in the central nervous system (CNS), and whether astrocytes can be harnessed for regenerative medicine to promote myelination. 4 Our study 5 describes a novel method of differentiation of human induced pluripotent stem cells (hiPSCs) to astroglia for promoting oligodendrocyte regeneration and remyelination therapy. We first demonstrate that the hiPSC-derived immature, rather than mature, human astroglia promote cell lineage progression of the oligodendrocyte progenitor cells (OPCs) cultured from mouse brain tissue via increased secretion of tissue inhibitor of metalloproteinase-1 (TIMP-1) and further develop astroglia therapies to promote myelin regeneration from endogenous resident OPCs in the brain. We find that immature human astrocytes have greater capacity in promoting OPC proliferation than mature human astrocytes. Furthermore, immature human astrocytes, but not mature human astrocytes, robustly boost OPC differentiation to oligodendrocytes (Fig. 1). In addition, we provide both in vitro and in vivo evidence that TIMP-1 partially, but critically, mediates the effects of immature astrocytes o...

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hESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury

Cited by 75 publications

References 54 publications

Generation of human pluripotent stem cell reporter lines for the isolation of and reporting on astrocytes generated from ventral midbrain and ventral spinal cord neural progenitors

Generation of human pluripotent stem cell reporter lines for the isolation of and reporting on astrocytes generated from ventral midbrain and ventral spinal cord neural progenitors

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Regenerating white matter using human iPSC-derived immature astroglia

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