Long-Term Proliferation and Dopaminergic Differentiation of Human Mesencephalic Neural Precursor Cells

Storch, Alexander; Paul, Gesine; Csete, Marie; Boehm, Bernhard O.; Carvey, Paul M.; Kupsch, Andreas; Schwarz, Johannes

doi:10.1006/exnr.2001.7706

Cited by 264 publications

(251 citation statements)

References 37 publications

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“…The lowered oxygen-induced enhancement of the NSC activity observed in our present study was consistent with previous reports demonstrating that the growth of neural crest stem cells, neuronal progenitor cells or mesencephalic precursor cells is enhanced in lowered oxygen (3-5%) when compared with high oxygen concentration (20%) (Morrison et al 2000;Shingo et al 2001;Storch et al 2001;Studer et al 2000).…”

Section: Discussionsupporting

confidence: 93%

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Effects of Oxygen Concentration on the Proliferation and Differentiation of Mouse Neural Stem Cells In Vitro

Horie

Moriya

et al. 2008

Cell Mol Neurobiol

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Section: Discussionsupporting

confidence: 93%

“…Storch and colleagues also reported the dopaminergic differentiation from human mesencephalic neural precursor cells in low oxygen conditions (Storch et al 2001). …”

Section: Discussionmentioning

confidence: 98%

Effects of Oxygen Concentration on the Proliferation and Differentiation of Mouse Neural Stem Cells In Vitro

Horie

Moriya

et al. 2008

Cell Mol Neurobiol

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“…Oxygen is one of the main regulators of proliferation and maintenance of stem cells, including midbrain dopaminergic NPCs in vitro [15,18,19]. To understand the role of oxygen in dopaminergic neurogenesis, we first investigated the possibility of transmission of maternal hypoxia and hyperoxia toward the developing brains in an in vivo mouse model.…”

Section: Different External Oxygen Environments Affect the Oxygen Levmentioning

confidence: 99%

“…Low atmospheric oxygen levels of 3% confer long-term proliferation and stem cell maintenance of midbrain dopaminergic NPCs in vitro, including the conservation of their dopaminergic differentiation potential, and avoid senescence in various species, including mouse [18][19][20][21][22][23][24]. Further in vitro studies have shown that the oxygen-dependent transcription factor hypoxiainducible factor 1a (HIF-1a) is involved in these processes [15,25,26] and is responsible for the initial adaptive response of cells to oxygen variations [27,28].…”

Section: Introductionmentioning

confidence: 99%

Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

WagenführLisa

Karen

MarroneLara

et al. 2016

Stem Cells and Development

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Oxygen tension is an important factor controlling stem cell proliferation and maintenance in various stem cell populations with a particular relevance in midbrain dopaminergic progenitors. Further studies have shown that the oxygen-dependent transcription factor hypoxia-inducible factor 1a (HIF-1a) is involved in these processes. However, all available studies on oxygen effects in dopaminergic neuroprogenitors were performed in vitro and thus it remains unclear whether tissue oxygen tension in the embryonic midbrain is also relevant for the regulation of dopaminergic neurogenesis in vivo. We thus dissect here the effects of oxygen tension in combination with HIF-1a conditional knockout on dopaminergic neurogenesis by using a novel experimental design allowing for the control of oxygen tension within the microenvironment of the neurogenic niche of the murine fetal midbrain in vivo. The microenvironment of the midbrain dopaminergic neurogenic niche was detected as hypoxic with oxygen tensions below 1.1%. Maternal oxygen treatment of 10%, 21%, and 75% atmospheric oxygen tension for 48 h translates into robust changes in fetal midbrain oxygenation. Fetal midbrain hypoxia hampered the generation of dopaminergic neurons and is accompanied with restricted fetal midbrain development. In contrast, induced hyperoxia stimulated proliferation and differentiation of dopaminergic progenitors during early and late embryogenesis. Oxygen effects were not directly mediated through HIF-1a signaling. These data-in agreement with in vitro data-indicate that oxygen is a crucial regulator of developmental dopaminergic neurogenesis. Our study provides the initial framework for future studies on molecular mechanisms mediating oxygen regulation of dopaminergic neurogenesis within the fetal midbrain as its natural environment.

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“…Several studies have focused on development of growth medium and expansion of hNPCs in small tissue culture flasks. [21][22][23][24][25] We have also successfully modified an existing serum-free cell growth medium (PPRF-m4) that was originally developed for the expansion of murine neural precursor cells (mNPCs) to now support the expansion of fetal hNPCs. hNPCs obtained from different regions of the fetal brain including the telencephalon, ventral mesencephalon, brain stem, and spinal cord have been expanded in both static culture and small-scale suspension bioreactors using this modified medium (PPRF-h2).…”

Section: Introductionmentioning

confidence: 99%

Expansion of Human Neural Precursor Cells in Large‐Scale Bioreactors for the Treatment of Neurodegenerative Disorders

Baghbaderani

Mukhida

Sen

et al. 2008

Biotechnology Progress

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The transplantation of in vitro expanded human neural precursor cells (hNPCs) represents a potential new treatment alternative for individuals suffering from incurable neurodegenerative disorders such as Parkinson's disease (PD) and Huntington's disease (HD). However, in order for cell restorative therapy to have widespread therapeutic significance, it will be necessary to generate unlimited quantities of clinical grade hNPCs in a standardized method. We report here that we have developed a serum‐free medium and scale‐up protocols that allow for the generation of clinical quantities of human telencephalon‐derived hNPCs in 500‐mL computer‐controlled suspension bioreactors. The average hNPC aggregate diameter in the bioreactors was maintained below a target value of 500 μm by controlling the liquid shear field. The human cells, which were inoculated at 105 cells/mL, exhibited a doubling time of 84 h, underwent a 36‐fold expansion over the course of 18 days, and maintained an average viability of over 90%. The bioreactor‐derived hNPCs retained their nestin expression following expansion and were able to differentiate into glial and neuronal phenotypes under defined conditions. It has also been demonstrated that these hNPCs differentiated to a GABAergic phenotype that has recently been shown to be able to restore functional behavior in rat models of HD and neuropathic pain (Mukhida, K. et al. Stem Cells 2007; DOI 10.1634/stemcells.2007–0326). This study demonstrates that clinical quantities of hNPCs can be successfully and reproducibly generated under standardized conditions in computer‐controlled suspension bioreactors.

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Long-Term Proliferation and Dopaminergic Differentiation of Human Mesencephalic Neural Precursor Cells

Cited by 264 publications

References 37 publications

Effects of Oxygen Concentration on the Proliferation and Differentiation of Mouse Neural Stem Cells In Vitro

Effects of Oxygen Concentration on the Proliferation and Differentiation of Mouse Neural Stem Cells In Vitro

Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

Expansion of Human Neural Precursor Cells in Large‐Scale Bioreactors for the Treatment of Neurodegenerative Disorders

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