Skip to main content

Advertisement

SpringerLink
Log in

A Tale of Two: When Neural Stem Cells Encounter Hypoxia

  • Review Paper
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Normoxia is defined as an oxygen concentration of 20.9%, as in room air, whereas hypoxia refers to any oxygen concentration less than this. Any physiological oxygen deficiency or tissue oxygen deficiency relative to demand is called hypoxia. Neural stem cells (NSCs) are multipotent stem cells that can differentiate into multiple cell lines such as neurons, oligodendrocytes, and astrocytes. Under hypoxic conditions, the apoptosis rate of NSCs increases remarkably in vitro or in vivo. However, some hypoxia promotes the proliferation and differentiation of NSCs. The difference is related to the oxygen concentration, the duration of hypoxia, the hypoxia tolerance threshold of the NSCs, and the tissue source of the NSCs. The main mechanism of hypoxia-induced proliferation and differentiation involves an increase in cyclin and erythropoietin concentrations, and hypoxia-inducible factors play a key role. Multiple molecular pathways are activated during hypoxia, including Notch, Wnt/β-catenin, PI3K/Akt, and altered microRNA expression. In addition, we review the protective effect of exogenous NSCs transplantation on ischemic or anoxic organs, the therapeutic potential of hypoxic preconditioning on exogenous NSCs and clinical application of NSCs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data Availability

Not applicable.

Code Availability

Not applicable.

References

  • Abbott LC, Nigussie F (2020) Adult neurogenesis in the mammalian dentate gyrus. Anat Histol Embryol 49:3–16

    PubMed  Google Scholar 

  • Acker T, Acker H (2004) Cellular oxygen sensing need in CNS function: physiological and pathological implications. J Exp Biol 207:3171–3188

    CAS  PubMed  Google Scholar 

  • Ali AAH, Abdel-Hafiz L, Tundo-Lavalle F et al (2021) P2Y2 deficiency impacts adult neurogenesis and related forebrain functions. FASEB J 35:e21546

    CAS  PubMed  Google Scholar 

  • An WG, Kanekal M, Simon MC et al (1998) Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392:405–408

    CAS  PubMed  Google Scholar 

  • Andreotti JP, Silva WN, Costa AC et al (2019) Neural stem cell niche heterogeneity. Semin Cell Dev Biol 95:42–53

    PubMed  PubMed Central  Google Scholar 

  • Androutsellis-Theotokis A, Leker RR, Soldner F et al (2006) Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442:823–826

    CAS  PubMed  Google Scholar 

  • Austin SHL, Gabarró-Solanas R, Rigo P et al (2021) Wnt/β-catenin signalling is dispensable for adult neural stem cell homeostasis and activation. Development 148:dev199629

    CAS  PubMed  PubMed Central  Google Scholar 

  • Baker EW, Platt SR, Lau VW et al (2017) Induced pluripotent stem cell-derived neural stem cell therapy enhances recovery in an ischemic stroke pig model. Sci Rep 7:10075

    PubMed  PubMed Central  Google Scholar 

  • Bartoli-Leonard F, Wilkinson FL, Langford-Smith AWW et al (2018) The interplay of SIRT1 and Wnt signaling in vascular calcification. Front Cardiovasc Med 5:183

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bengoa-Vergniory N, Kypta RM (2015) Canonical and noncanonical Wnt signaling in neural stem/progenitor cells. Cell Mol Life Sci 72:4157–4172

    CAS  PubMed  Google Scholar 

  • Bergeron M, Yu AY, Solway KE et al (1999) Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain. Eur J Neurosci 11:4159–4170

    CAS  PubMed  Google Scholar 

  • Bernaudin M, Nedelec A-S, Divoux D et al (2002) Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab 22:393–403

    CAS  PubMed  Google Scholar 

  • Bobkova NV, Poltavtseva RA, Leonov SV et al (2020) Neuroregeneration: regulation in neurodegenerative diseases and aging. Biochemistry (Mosc) 85:S108–S130

    CAS  PubMed  Google Scholar 

  • Borlongan CV, Hadman M, Sanberg CD et al (2004) Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke 35:2385–2389

    PubMed  Google Scholar 

  • Braccioli L, Heijnen CJ, Coffer PJ et al (2017) Delayed administration of neural stem cells after hypoxia-ischemia reduces sensorimotor deficits, cerebral lesion size, and neuroinflammation in neonatal mice. Pediatr Res 81:127–135

    PubMed  Google Scholar 

  • Braunschweig L, Meyer AK, Wagenführ L et al (2015) Oxygen regulates proliferation of neural stem cells through Wnt/β-catenin signalling. Mol Cell Neurosci 67:84–92

    CAS  PubMed  Google Scholar 

  • Bravo-Ferrer I, Cuartero MI, Zarruk JG et al (2017) Cannabinoid type-2 receptor drives neurogenesis and improves functional outcome after stroke. Stroke 48:204–212

    CAS  PubMed  Google Scholar 

  • Bühnemann C, Scholz A, Bernreuther C et al (2006) Neuronal differentiation of transplanted embryonic stem cell-derived precursors in stroke lesions of adult rats. Brain 129:3238–3248

    PubMed  Google Scholar 

  • Bürgers HF, Schelshorn DW, Wagner W et al (2008) Acute anoxia stimulates proliferation in adult neural stem cells from the rat brain. Exp Brain Res 188:33–43

    PubMed  Google Scholar 

  • Camps C, Saini HK, Mole DR et al (2014) Integrated analysis of microRNA and mRNA expression and association with HIF binding reveals the complexity of microRNA expression regulation under hypoxia. Mol Cancer 13:28

    PubMed  PubMed Central  Google Scholar 

  • Chavali PL, Saini RKR, Matsumoto Y et al (2011) Nuclear orphan receptor TLX induces Oct-3/4 for the survival and maintenance of adult hippocampal progenitors upon hypoxia. J Biol Chem 286:9393–9404

    CAS  PubMed  Google Scholar 

  • Chen H-L, Pistollato F, Hoeppner DJ et al (2007) Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells 25:2291–2301

    PubMed  Google Scholar 

  • Chen X, Tian Y, Yao L et al (2010) Hypoxia stimulates proliferation of rat neural stem cells with influence on the expression of cyclin D1 and c-Jun N-terminal protein kinase signaling pathway in vitro. Neuroscience 165:705–714

    CAS  PubMed  Google Scholar 

  • Chen L, Zhang G, Gu Y et al (2016) Meta-analysis and systematic review of neural stem cells therapy for experimental ischemia stroke in preclinical studies. Sci Rep 6:32291

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Li X, Zhang W et al (2018) Activation of AMPK inhibits inflammatory response during hypoxia and reoxygenation through modulating JNK-mediated NF-κB pathway. Metabolism 83:256–270

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng Y, Zhang J, Deng L et al (2015) Intravenously delivered neural stem cells migrate into ischemic brain, differentiate and improve functional recovery after transient ischemic stroke in adult rats. Int J Clin Exp Pathol 8:2928–2936

    PubMed  PubMed Central  Google Scholar 

  • Choudhry H, Harris AL (2018) Advances in hypoxia-inducible factor biology. Cell Metab 27:281–298

    CAS  PubMed  Google Scholar 

  • Chu CT (2008) Eaten alive: autophagy and neuronal cell death after hypoxia-ischemia. Am J Pathol 172:284–287

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chung H, Choi J, Park S (2018) Ghrelin protects adult rat hippocampal neural stem cells from excessive autophagy during oxygen-glucose deprivation. Endocr J 65:63–73

    PubMed  Google Scholar 

  • Cifuentes D, Xue H, Taylor DW et al (2010) A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328:1694–1698

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coughlan C, Bruce KD, Burgy O et al (2020) Exosome isolation by ultracentrifugation and precipitation and techniques for downstream analyses. Curr Protoc Cell Biol 88:e110

    CAS  PubMed  PubMed Central  Google Scholar 

  • Coumans FAW, Brisson AR, Buzas EI et al (2017) Methodological guidelines to study extracellular vesicles. Circ Res 120:1632–1648

    CAS  PubMed  Google Scholar 

  • Cui X-P, Xing Y, Chen J-M et al (2011) Wnt/beta-catenin is involved in the proliferation of hippocampal neural stem cells induced by hypoxia. Ir J Med Sci 180:387–393

    CAS  PubMed  Google Scholar 

  • Daadi MM, Maag A-L, Steinberg GK (2008) Adherent self-renewable human embryonic stem cell-derived neural stem cell line: functional engraftment in experimental stroke model. PLoS ONE 3:e1644

    PubMed  PubMed Central  Google Scholar 

  • Daadi MM, Li Z, Arac A et al (2009) Molecular and magnetic resonance imaging of human embryonic stem cell-derived neural stem cell grafts in ischemic rat brain. Mol Ther 17:1282–1291

    CAS  PubMed  PubMed Central  Google Scholar 

  • Descloux C, Ginet V, Clarke PGH et al (2015) Neuronal death after perinatal cerebral hypoxia-ischemia: focus on autophagy-mediated cell death. Int J Dev Neurosci 45:75–85

    CAS  PubMed  Google Scholar 

  • Devlin C, Greco S, Martelli F et al (2011) miR-210: more than a silent player in hypoxia. IUBMB Life 63:94–100

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ding Z, Zhang J, Hu Y et al (2021) Effects of PI3K/AKT/mTOR pathway regulation of HIF-1α on lanthanum-induced neurotoxicity in rats. Brain Res 1761(3):147400

    CAS  Google Scholar 

  • Doyle LM, Wang MZ (2019) Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells 8:E727

    Google Scholar 

  • Dupont G, Combettes L, Bird GS et al (2011) Calcium oscillations. Cold Spring Harb Perspect Biol 3:a004226

    PubMed  PubMed Central  Google Scholar 

  • Galochkina T, Ng Fuk Chong M, Challali L et al (2019) New insights into GluT1 mechanics during glucose transfer. Sci Rep 9:998

    PubMed  PubMed Central  Google Scholar 

  • Gomez J, Holmes N, Hansen A et al (2022) Mathematical modeling of therapeutic neural stem cell migration in mouse brain with and without brain tumors. Math Biosci Eng 19:2592–2615

    PubMed  PubMed Central  Google Scholar 

  • Greco S, Gaetano C, Martelli F (2014) HypoxamiR regulation and function in ischemic cardiovascular diseases. Antioxid Redox Signal 21:1202–1219

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grote HE, Hannan AJ (2007) Regulators of adult neurogenesis in the healthy and diseased brain. Clin Exp Pharmacol Physiol 34:533–545

    CAS  PubMed  Google Scholar 

  • Gustafsson MV, Zheng X, Pereira T et al (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9:617–628

    CAS  PubMed  Google Scholar 

  • György B, Hung ME, Breakefield XO et al (2015) Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol 55:439–464

    PubMed  Google Scholar 

  • Harms KM, Li L, Cunningham LA (2010) Murine neural stem/progenitor cells protect neurons against ischemia by HIF-1alpha-regulated VEGF signaling. PLoS ONE 5:e9767

    PubMed  PubMed Central  Google Scholar 

  • Hori J, Ng TF, Shatos M et al (2003) Neural progenitor cells lack immunogenicity and resist destruction as allografts. Stem Cells 21:405–416

    PubMed  Google Scholar 

  • Horie N, So K, Moriya T et al (2008) Effects of oxygen concentration on the proliferation and differentiation of mouse neural stem cells in vitro. Cell Mol Neurobiol 28:833–845

    CAS  PubMed  Google Scholar 

  • Hu Z, Li F, Zhou X et al (2020) Momordica charantia polysaccharides modulate the differentiation of neural stem cells via SIRT1/Β-catenin axis in cerebral ischemia/reperfusion. Stem Cell Res Ther 11:485

    PubMed  PubMed Central  Google Scholar 

  • Huang L, Zhang L (2019) Neural stem cell therapies and hypoxic-ischemic brain injury. Prog Neurobiol 173:1–17

    CAS  PubMed  Google Scholar 

  • Huang X, Ding L, Bennewith KL et al (2009) Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell 35:856–867

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y, Chen S, Luo Y et al (2020) Crosstalk between Inflammation and the BBB in stroke. Curr Neuropharmacol 18:1227–1236

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hwang IK, Yoo K-Y, Han TH et al (2009) Enhanced cell proliferation and neuroblast differentiation in the rat hippocampal dentate gyrus following myocardial infarction. Neurosci Lett 450:275–280

    CAS  PubMed  Google Scholar 

  • Imai S, Guarente L (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464–471

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ji G, Liu M, Zhao X-F et al (2015) NF-κB signaling is involved in the effects of intranasally engrafted human neural stem cells on neurofunctional improvements in neonatal rat hypoxic-ischemic encephalopathy. CNS Neurosci Ther 21:926–935

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang Q, Geng X, Warren J et al (2020) Hypoxia inducible factor-1α (HIF-1α) mediates NLRP3 inflammasome-dependent-pyroptotic and apoptotic cell death following ischemic stroke. Neuroscience 448:126–139

    CAS  PubMed  Google Scholar 

  • Jiao Q, Li X, An J et al (2017) Cell–cell connection enhances proliferation and neuronal differentiation of rat embryonic neural stem/progenitor cells. Front Cell Neurosci 11:200

    PubMed  PubMed Central  Google Scholar 

  • Jin K, Minami M, Lan JQ et al (2001) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci USA 98:4710–4715

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jin K, Mao XO, Zhu Y et al (2002) MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad. J Neurochem 80:119–125

    CAS  PubMed  Google Scholar 

  • Joo H-Y, Yun M, Jeong J et al (2015) SIRT1 deacetylates and stabilizes hypoxia-inducible factor-1α (HIF-1α) via direct interactions during hypoxia. Biochem Biophys Res Commun 462:294–300

    CAS  PubMed  Google Scholar 

  • Kahroba H, Ramezani B, Maadi H et al (2021) The role of Nrf2 in neural stem/progenitors cells: from maintaining stemness and self-renewal to promoting differentiation capability and facilitating therapeutic application in neurodegenerative disease. Ageing Res Rev 65:101211

    CAS  PubMed  Google Scholar 

  • Kalladka D, Sinden J, Pollock K et al (2016) Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet 388:787–796

    PubMed  Google Scholar 

  • Kalladka D, Sinden J, McLean J et al (2019) Increased deep grey matter functional connectivity of poststroke hNSC implanted ipsilesional putamen. J Neurol Neurosurg Psychiatry 90:959–960

    PubMed  Google Scholar 

  • Keeley TP, Mann GE (2019) Defining physiological normoxia for improved translation of cell physiology to animal models and humans. Physiol Rev 99:161–234

    CAS  PubMed  Google Scholar 

  • Khacho M, Harris R, Slack RS (2019) Mitochondria as central regulators of neural stem cell fate and cognitive function. Nat Rev Neurosci 20:34–48

    CAS  PubMed  Google Scholar 

  • Kim D-E, Tsuji K, Kim YR et al (2006) Neural stem cell transplant survival in brains of mice: assessing the effect of immunity and ischemia by using real-time bioluminescent imaging. Radiology 241:822–830

    PubMed  Google Scholar 

  • Kim HJ, Joe Y, Yu JK et al (2015) Carbon monoxide protects against hepatic ischemia/reperfusion injury by modulating the miR-34a/SIRT1 pathway. Biochim Biophys Acta 1852:1550–1559

    CAS  PubMed  Google Scholar 

  • King D, Yeomanson D, Bryant HE (2015) PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J Pediatr Hematol Oncol 37:245–251

    CAS  PubMed  Google Scholar 

  • Koch U, Lehal R, Radtke F (2013) Stem cells living with a Notch. Development 140:689–704

    CAS  PubMed  Google Scholar 

  • Koch-Nolte F, Kernstock S, Mueller-Dieckmann C et al (2008) Mammalian ADP-ribosyltransferases and ADP-ribosylhydrolases. Front Biosci 13:6716–6729

    CAS  PubMed  Google Scholar 

  • Kulshreshtha R, Ferracin M, Wojcik SE et al (2007) A microRNA signature of hypoxia. Mol Cell Biol 27:1859–1867

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lai CP-K, Breakefield XO (2012) Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front Physiol 3:228

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lange C, Mix E, Rateitschak K et al (2006) Wnt signal pathways and neural stem cell differentiation. Neurodegener Dis 3:76–86

    CAS  PubMed  Google Scholar 

  • Lange C, Turrero Garcia M, Decimo I et al (2016) Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis. EMBO J 35:924–941

    CAS  PubMed  PubMed Central  Google Scholar 

  • Laughner E, Taghavi P, Chiles K et al (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1alpha (HIF-1alpha) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995–4004

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee S, Tong L, Denu JM (2008) Quantification of endogenous sirtuin metabolite O-acetyl-ADP-ribose. Anal Biochem 383:174–179

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li L, Qu Y, Mao M et al (2008) The involvement of phosphoinositid 3-kinase/Akt pathway in the activation of hypoxia-inducible factor-1alpha in the developing rat brain after hypoxia-ischemia. Brain Res 1197:152–158

    CAS  PubMed  Google Scholar 

  • Li L, Candelario KM, Thomas K et al (2014) Hypoxia inducible factor-1α (HIF-1α) is required for neural stem cell maintenance and vascular stability in the adult mouse SVZ. J Neurosci 34:16713–16719

    PubMed  PubMed Central  Google Scholar 

  • Li Y, Wu L, Yu M et al (2018) HIF-1α is critical for the activation of notch signaling in neurogenesis during acute epilepsy. Neuroscience 394:206–219

    CAS  PubMed  Google Scholar 

  • Li F, Zhang J, Liao R et al (2020a) Mesenchymal stem cell-derived extracellular vesicles prevent neural stem cell hypoxia injury via promoting miR-210-3p expression. Mol Med Rep 22:3813–3821

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li X, Peng Z, Long L et al (2020b) Wnt4-modified NSC transplantation promotes functional recovery after spinal cord injury. FASEB J 34:82–94

    PubMed  Google Scholar 

  • Li F, Zhang J, Chen A et al (2021a) Combined transplantation of neural stem cells and bone marrow mesenchymal stem cells promotes neuronal cell survival to alleviate brain damage after cardiac arrest via microRNA-133b incorporated in extracellular vesicles. Aging (Albany NY) 13:262–278

    PubMed  Google Scholar 

  • Li G, Liu J, Guan Y et al (2021b) The role of hypoxia in stem cell regulation of the central nervous system: from embryonic development to adult proliferation. CNS Neurosci Ther 27:1446–1457

    PubMed  PubMed Central  Google Scholar 

  • Lin G-Q, He X-F, Liang F-Y et al (2018) Transplanted human neural precursor cells integrate into the host neural circuit and ameliorate neurological deficits in a mouse model of traumatic brain injury. Neurosci Lett 674:11–17

    CAS  PubMed  Google Scholar 

  • Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568

    CAS  PubMed  Google Scholar 

  • Liu Z, Yang G, Zhao T et al (2011) Small ncRNA expression and regulation under hypoxia in neural progenitor cells. Cell Mol Neurobiol 31:1–5

    PubMed  Google Scholar 

  • Liu L, Wang P, Liu X et al (2014a) Exogenous NAD(+) supplementation protects H9c2 cardiac myoblasts against hypoxia/reoxygenation injury via Sirt1-p53 pathway. Fundam Clin Pharmacol 28:180–189

    CAS  PubMed  Google Scholar 

  • Liu Y, Nie H, Zhang K et al (2014b) A feedback regulatory loop between HIF-1α and miR-21 in response to hypoxia in cardiomyocytes. FEBS Lett 588:3137–3146

    CAS  PubMed  Google Scholar 

  • Liu Y, Li X, Zhu S et al (2015) Ectopic expression of miR-494 inhibited the proliferation, invasion and chemoresistance of pancreatic cancer by regulating SIRT1 and c-Myc. Gene Ther 22:729–738

    CAS  PubMed  Google Scholar 

  • Liu Q, Li Y, Zhou L et al (2018) GRP78 promotes neural stem cell antiapoptosis and survival in response to oxygen-glucose deprivation (OGD)/reoxygenation through PI3K/Akt, ERK1/2, and NF-κB/p65 pathways. Oxid Med Cell Longev 2018:3541807

    PubMed  PubMed Central  Google Scholar 

  • Lu S, Li K, Yang Y et al (2022) Optimization of an intranasal route for the delivery of human neural stem cells to treat a neonatal hypoxic-ischemic brain injury rat model. Neuropsychiatr Dis Treat 18:413–426

    CAS  PubMed  PubMed Central  Google Scholar 

  • Luo M-L, Pan L, Wang L et al (2019) Transplantation of NSCs promotes the recovery of cognitive functions by regulating neurotransmitters in rats with traumatic brain injury. Neurochem Res 44:2765–2775

    CAS  PubMed  Google Scholar 

  • Madanecki P, Kapoor N, Bebok Z et al (2013) Regulation of angiogenesis by hypoxia: the role of microRNA. Cell Mol Biol Lett 18:47–57

    CAS  PubMed  Google Scholar 

  • Malacrida S, Giannella A, Ceolotto G et al (2019) Transcription factors regulation in human peripheral white blood cells during hypobaric hypoxia exposure: an in vivo experimental study. Sci Rep 9:9901

    PubMed  PubMed Central  Google Scholar 

  • Malhotra H, Sheokand N, Kumar S et al (2016) Exosomes: tunable nano vehicles for macromolecular delivery of transferrin and lactoferrin to specific intracellular compartment. J Biomed Nanotechnol 12:1101–1114

    CAS  PubMed  Google Scholar 

  • Marchetti B, Tirolo C, L’Episcopo F et al (2020) Parkinson’s disease, aging and adult neurogenesis: Wnt/β-catenin signalling as the key to unlock the mystery of endogenous brain repair. Aging Cell 19:e13101

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mazumdar J, O’Brien WT, Johnson RS et al (2010) O2 regulates stem cells through Wnt/β-catenin signalling. Nat Cell Biol 12:1007–1013

    CAS  PubMed  PubMed Central  Google Scholar 

  • McGettrick AF, O’Neill LAJ (2020) The role of HIF in immunity and inflammation. Cell Metab 32:524–536

    CAS  PubMed  Google Scholar 

  • Meng Z, Li J, Zhao H et al (2015) Resveratrol relieves ischemia-induced oxidative stress in the hippocampus by activating SIRT1. Exp Ther Med 10:525–530

    CAS  PubMed  PubMed Central  Google Scholar 

  • Moreno M, Fernández V, Monllau JM et al (2015) Transcriptional profiling of hypoxic neural stem cells identifies calcineurin-NFATc4 signaling as a major regulator of neural stem cell biology. Stem Cell Rep 5:157–165

    CAS  Google Scholar 

  • Muir KW, Bulters D, Willmot M et al (2020) Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2). J Neurol Neurosurg Psychiatry 91:396–401

    PubMed  Google Scholar 

  • Mutoh T, Sanosaka T, Ito K et al (2012) Oxygen levels epigenetically regulate fate switching of neural precursor cells via hypoxia-inducible factor 1α-notch signal interaction in the developing brain. Stem Cells 30:561–569

    CAS  PubMed  Google Scholar 

  • Nakayama K, Kataoka N (2019) Regulation of gene expression under hypoxic conditions. Int J Mol Sci 20:E3278

    Google Scholar 

  • Nasser M, Ballout N, Mantash S et al (2018) Transplantation of embryonic neural stem cells and differentiated cells in a controlled cortical impact (CCI) model of adult mouse somatosensory cortex. Front Neurol 9:895

    PubMed  PubMed Central  Google Scholar 

  • Obernier K, Alvarez-Buylla A (2019) Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain. Development 146:dev156059

    CAS  PubMed  PubMed Central  Google Scholar 

  • Oki K, Tatarishvili J, Wood J et al (2012) Human-induced pluripotent stem cells form functional neurons and improve recovery after grafting in stroke-damaged brain. Stem Cells 30:1120–1133

    CAS  PubMed  Google Scholar 

  • Othman FA, Tan SC (2020) Preconditioning strategies to enhance neural stem cell-based therapy for ischemic stroke. Brain Sci 10:E893

    Google Scholar 

  • Ottoboni L, von Wunster B, Martino G (2020) Therapeutic plasticity of neural stem cells. Front Neurol 11:148

    PubMed  PubMed Central  Google Scholar 

  • Oya S, Yoshikawa G, Takai K et al (2009) Attenuation of Notch signaling promotes the differentiation of neural progenitors into neurons in the hippocampal CA1 region after ischemic injury. Neuroscience 158:683–692

    CAS  PubMed  Google Scholar 

  • Palma-Tortosa S, García-Culebras A, Moraga A et al (2017) Specific features of SVZ neurogenesis after cortical ischemia: a longitudinal study. Sci Rep 7:16343

    CAS  PubMed  PubMed Central  Google Scholar 

  • Panchision DM (2009) The role of oxygen in regulating neural stem cells in development and disease. J Cell Physiol 220:562–568

    CAS  PubMed  Google Scholar 

  • Parent JM, Vexler ZS, Gong C et al (2002) Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 52:802–813

    PubMed  Google Scholar 

  • Pawson T, Nash P (2000) Protein–protein interactions define specificity in signal transduction. Genes Dev 14:1027–1047

    CAS  PubMed  Google Scholar 

  • Pellegrino G, Trubert C, Terrien J et al (2018) A comparative study of the neural stem cell niche in the adult hypothalamus of human, mouse, rat and gray mouse lemur (Microcebus murinus). J Comp Neurol 526:1419–1443

    CAS  PubMed  Google Scholar 

  • Pistollato F, Chen H-L, Schwartz PH et al (2007) Oxygen tension controls the expansion of human CNS precursors and the generation of astrocytes and oligodendrocytes. Mol Cell Neurosci 35:424–435

    CAS  PubMed  Google Scholar 

  • Pistollato F, Rampazzo E, Persano L et al (2010) Interaction of hypoxia-inducible factor-1α and Notch signaling regulates medulloblastoma precursor proliferation and fate. Stem Cells 28:1918–1929

    CAS  PubMed  Google Scholar 

  • Pugh CW, Ratcliffe PJ (2017) New horizons in hypoxia signaling pathways. Exp Cell Res 356:116–121

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qi C, Zhang J, Chen X et al (2017) Hypoxia stimulates neural stem cell proliferation by increasing HIF-1α expression and activating Wnt/β-catenin signaling. Cell Mol Biol (Noisy-le-grand) 63:12–19

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ran M, Li Z, Yang L et al (2015) Calorie restriction attenuates cerebral ischemic injury via increasing SIRT1 synthesis in the rat. Brain Res 1610:61–68

    CAS  PubMed  Google Scholar 

  • Robbins PD, Dorronsoro A, Booker CN (2016) Regulation of chronic inflammatory and immune processes by extracellular vesicles. J Clin Investig 126:1173–1180

    PubMed  PubMed Central  Google Scholar 

  • Roitbak T, Li L, Cunningham LA (2008) Neural stem/progenitor cells promote endothelial cell morphogenesis and protect endothelial cells against ischemia via HIF-1alpha-regulated VEGF signaling. J Cereb Blood Flow Metab 28:1530–1542

    CAS  PubMed  Google Scholar 

  • Rosenbloom AB, Tarczyński M, Lam N et al (2020) β-Catenin signaling dynamics regulate cell fate in differentiating neural stem cells. Proc Natl Acad Sci USA 117:28828–28837

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rosenblum S, Wang N, Smith TN et al (2012) Timing of intra-arterial neural stem cell transplantation after hypoxia-ischemia influences cell engraftment, survival, and differentiation. Stroke 43:1624–1631

    CAS  PubMed  Google Scholar 

  • Rosenblum S, Smith TN, Wang N et al (2015) BDNF pretreatment of human embryonic-derived neural stem cells improves cell survival and functional recovery after transplantation in hypoxic-ischemic stroke. Cell Transplant 24:2449–2461

    PubMed  Google Scholar 

  • Ryu S, Lee S-H, Kim SU et al (2016) Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain. Neural Regen Res 11:298–304

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ryu DR, Yu MR, Kong KH et al (2019) Sirt1-hypoxia-inducible factor-1α interaction is a key mediator of tubulointerstitial damage in the aged kidney. Aging Cell 18:e12904

    PubMed  PubMed Central  Google Scholar 

  • Sakata H, Niizuma K, Wakai T et al (2012a) Neural stem cells genetically modified to overexpress Cu/Zn-superoxide dismutase enhance amelioration of ischemic stroke in mice. Stroke 43:2423–2429

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sakata H, Niizuma K, Yoshioka H et al (2012b) Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats. J Neurosci 32:3462–3473

    CAS  PubMed  PubMed Central  Google Scholar 

  • Santilli G, Lamorte G, Carlessi L et al (2010) Mild hypoxia enhances proliferation and multipotency of human neural stem cells. PLoS ONE 5:e8575

    PubMed  PubMed Central  Google Scholar 

  • Sato Y, Nakanishi K, Hayakawa M et al (2008) Reduction of brain injury in neonatal hypoxic-ischemic rats by intracerebroventricular injection of neural stem/progenitor cells together with chondroitinase ABC. Reprod Sci 15:613–620

    PubMed  Google Scholar 

  • Serocki M, Bartoszewska S, Janaszak-Jasiecka A et al (2018) miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target. Angiogenesis 21:183–202

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shabani Z, Ghadiri T, Karimipour M et al (2021) Modulatory properties of extracellular matrix glycosaminoglycans and proteoglycans on neural stem cells behavior: highlights on regenerative potential and bioactivity. Int J Biol Macromol 171:366–381

    CAS  PubMed  Google Scholar 

  • Shi Z, Wei Z, Li J et al (2018) Identification and verification of candidate genes regulating neural stem cells behavior under hypoxia. Cell Physiol Biochem 47:212–222

    CAS  PubMed  Google Scholar 

  • Shinoyama M, Ideguchi M, Kida H et al (2013) Cortical region-specific engraftment of embryonic stem cell-derived neural progenitor cells restores axonal sprouting to a subcortical target and achieves motor functional recovery in a mouse model of neonatal hypoxic-ischemic brain injury. Front Cell Neurosci 7:128

    CAS  PubMed  PubMed Central  Google Scholar 

  • Simão F, Matté A, Matté C et al (2011) Resveratrol prevents oxidative stress and inhibition of Na(+)K(+)-ATPase activity induced by transient global cerebral ischemia in rats. J Nutr Biochem 22:921–928

    PubMed  Google Scholar 

  • Stockmann C, Fandrey J (2006) Hypoxia-induced erythropoietin production: a paradigm for oxygen-regulated gene expression. Clin Exp Pharmacol Physiol 33:968–979

    CAS  PubMed  Google Scholar 

  • Studer L, Csete M, Lee SH et al (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci 20:7377–7383

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sun D, Gugliotta M, Rolfe A et al (2011) Sustained survival and maturation of adult neural stem/progenitor cells after transplantation into the injured brain. J Neurotrauma 28:961–972

    PubMed  PubMed Central  Google Scholar 

  • Sun C, Fu J, Qu Z et al (2019) Chronic mild hypoxia promotes hippocampal neurogenesis involving Notch1 signaling in epileptic rats. Brain Res 1714:88–98

    CAS  PubMed  Google Scholar 

  • Suzuki H, Tomida A, Tsuruo T (2001) Dephosphorylated hypoxia-inducible factor 1alpha as a mediator of p53-dependent apoptosis during hypoxia. Oncogene 20:5779–5788

    CAS  PubMed  Google Scholar 

  • Tang Y, Wang J, Lin X et al (2014) Neural stem cell protects aged rat brain from ischemia–reperfusion injury through neurogenesis and angiogenesis. J Cereb Blood Flow Metab 34:1138–1147

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tang Y, Yu P, Cheng L (2017) Current progress in the derivation and therapeutic application of neural stem cells. Cell Death Dis 8:e3108

    CAS  PubMed  PubMed Central  Google Scholar 

  • Terraneo L, Paroni R, Bianciardi P et al (2017) Brain adaptation to hypoxia and hyperoxia in mice. Redox Biol 11:12–20

    CAS  PubMed  Google Scholar 

  • Thrash-Bingham CA, Tartof KD (1999) aHIF: a natural antisense transcript overexpressed in human renal cancer and during hypoxia. J Natl Cancer Inst 91:143–151

    CAS  PubMed  Google Scholar 

  • Trebec-Reynolds DP, Voronov I, Heersche JNM et al (2010) VEGF-A expression in osteoclasts is regulated by NF-kappaB induction of HIF-1alpha. J Cell Biochem 110:343–351

    CAS  PubMed  Google Scholar 

  • Tseng K-Y, Anttila JE, Khodosevich K et al (2018) MANF promotes differentiation and migration of neural progenitor cells with potential neural regenerative effects in stroke. Mol Ther 26:238–255

    CAS  PubMed  Google Scholar 

  • Tunç BS, Toprak F, Toprak SF et al (2021) In vitro investigation of growth factors including MGF and IGF-1 in neural stem cell activation, proliferation, and migration. Brain Res 1759:147366

    PubMed  Google Scholar 

  • Uchida T, Rossignol F, Matthay MA et al (2004) Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression in lung epithelial cells: implication of natural antisense HIF-1alpha. J Biol Chem 279:14871–14878

    CAS  PubMed  Google Scholar 

  • Urbán N, Guillemot F (2014) Neurogenesis in the embryonic and adult brain: same regulators, different roles. Front Cell Neurosci 8:396

    PubMed  PubMed Central  Google Scholar 

  • Wakai T, Narasimhan P, Sakata H et al (2016) Hypoxic preconditioning enhances neural stem cell transplantation therapy after intracerebral hemorrhage in mice. J Cereb Blood Flow Metab 36:2134–2145

    CAS  PubMed  Google Scholar 

  • Wang F, Xiong L, Huang X et al (2013) miR-210 suppresses BNIP3 to protect against the apoptosis of neural progenitor cells. Stem Cell Res 11:657–667

    CAS  PubMed  Google Scholar 

  • Wang S-H, Li N, Wei Y et al (2014) β-Catenin deacetylation is essential for WNT-induced proliferation of breast cancer cells. Mol Med Rep 9:973–978

    CAS  PubMed  Google Scholar 

  • Wang Y, Zhang L, Li Y et al (2015a) Exosomes/microvesicles from induced pluripotent stem cells deliver cardioprotective miRNAs and prevent cardiomyocyte apoptosis in the ischemic myocardium. Int J Cardiol 192:61–69

    PubMed  PubMed Central  Google Scholar 

  • Wang Q, Yang L, Wang Y (2015b) Enhanced differentiation of neural stem cells to neurons and promotion of neurite outgrowth by oxygen-glucose deprivation. Int J Dev Neurosci 43:50–57

    PubMed  Google Scholar 

  • Wang Y, Pang Q-J, Liu J-T et al (2018) Down-regulated miR-448 relieves spinal cord ischemia/reperfusion injury by up-regulating SIRT1. Braz J Med Biol Res 51:e7319

    PubMed  PubMed Central  Google Scholar 

  • Wang M, Liang X, Cheng M et al (2019a) Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke. Cell Death Dis 10:561

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang D, Wang L, Bai L et al (2019b) Effects of inhibition of miR-155-5p in neural stem cell subarachnoid transplant on rats with cerebral infarction. Hum Gene Ther Methods 30:184–193

    CAS  PubMed  Google Scholar 

  • Wang M, Yu L, Zhu L-Y et al (2020) Cytokines induce monkey neural stem cell differentiation through Notch signaling. Biomed Res Int 2020:1308526

    PubMed  PubMed Central  Google Scholar 

  • Webb RL, Kaiser EE, Scoville SL et al (2018a) Human neural stem cell extracellular vesicles improve tissue and functional recovery in the murine thromboembolic stroke model. Transl Stroke Res 9:530–539

    CAS  PubMed  Google Scholar 

  • Webb RL, Kaiser EE, Jurgielewicz BJ et al (2018b) Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke. Stroke 49:1248–1256

    PubMed  PubMed Central  Google Scholar 

  • Wechsler LR, Bates D, Stroemer P et al (2018) Cell therapy for chronic stroke. Stroke 49:1066–1074

    PubMed  Google Scholar 

  • Wei ZZ, Zhu Y-B, Zhang JY et al (2017a) Priming of the cells: hypoxic preconditioning for stem cell therapy. Chin Med J (Engl) 130:2361–2374

    CAS  PubMed  Google Scholar 

  • Wei L, Wei ZZ, Jiang MQ et al (2017b) Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke. Prog Neurobiol 157:49–78

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wei N, Sun Z, Yu J et al (2021) Immunological responses to transgene-modified neural stem cells after transplantation. Front Immunol 12:697203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wick A, Wick W, Waltenberger J et al (2002) Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J Neurosci 22:6401–6407

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wu L-Y, He Y-L, Zhu L-L (2018) Possible role of PHD inhibitors as hypoxia-mimicking agents in the maintenance of neural stem cells’ self-renewal properties. Front Cell Dev Biol 6:169

    PubMed  PubMed Central  Google Scholar 

  • Xiao Y, Peng H, Hong C et al (2017) PDGF promotes the Warburg effect in pulmonary arterial smooth muscle cells via activation of the PI3K/AKT/mTOR/HIF-1α signaling pathway. Cell Physiol Biochem 42:1603–1613

    CAS  PubMed  Google Scholar 

  • Xie Y, Li W, Feng J et al (2016) MicroRNA-363 and GATA-1 are regulated by HIF-1α in K562 cells under hypoxia. Mol Med Rep 14:2503–2510

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong L, Zhao T, Huang X et al (2009) Heat shock protein 90 is involved in regulation of hypoxia-driven proliferation of embryonic neural stem/progenitor cells. Cell Stress Chaperones 14:183–192

    CAS  PubMed  Google Scholar 

  • Yagita Y, Kitagawa K, Ohtsuki T et al (2001) Neurogenesis by progenitor cells in the ischemic adult rat hippocampus. Stroke 32:1890–1896

    CAS  PubMed  Google Scholar 

  • Yan J, Goerne T, Zelmer A et al (2019) The RNA-binding protein RBM3 promotes neural stem cell (NSC) proliferation under hypoxia. Front Cell Dev Biol 7:288

    PubMed  PubMed Central  Google Scholar 

  • Yáñez-Mó M, Siljander PR-M, Andreu Z et al (2015) Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 4:27066

    PubMed  Google Scholar 

  • Yang Y, Li Y, Chen X et al (2016) Exosomal transfer of miR-30a between cardiomyocytes regulates autophagy after hypoxia. J Mol Med (Berl) 94:711–724

    CAS  PubMed  Google Scholar 

  • Yang Y, Liu Y, Wang Y et al (2022) Regulation of SIRT1 and its roles in inflammation. Front Immunol 13:831168

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yasui T, Uezono N, Nakashima H et al (2017) Hypoxia epigenetically confers astrocytic differentiation potential on human pluripotent cell-derived neural precursor cells. Stem Cell Rep 8:1743–1756

    CAS  Google Scholar 

  • Ye Q, Wu Y, Wu J et al (2018) Neural stem cells expressing bFGF reduce brain damage and restore sensorimotor function after neonatal hypoxia-ischemia. Cell Physiol Biochem 45:108–118

    CAS  PubMed  Google Scholar 

  • Zhang ZG, Chopp M (2016) Exosomes in stroke pathogenesis and therapy. J Clin Investig 126:1190–1197

    PubMed  PubMed Central  Google Scholar 

  • Zhang RL, Zhang ZG, Zhang L et al (2001) Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105:33–41

    CAS  PubMed  Google Scholar 

  • Zhang R, Zhang Z, Zhang C et al (2004) Stroke transiently increases subventricular zone cell division from asymmetric to symmetric and increases neuronal differentiation in the adult rat. J Neurosci 24:5810–5815

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang C, Zhu L, Zhao T et al (2006) Characteristics of neural stem cells expanded in lowered oxygen and the potential role of hypoxia-inducible factor-1alpha. Neurosignals 15:259–265

    CAS  PubMed  Google Scholar 

  • Zhang F, Ding T, Yu L et al (2012) Dexmedetomidine protects against oxygen-glucose deprivation-induced injury through the I2 imidazoline receptor-PI3K/AKT pathway in rat C6 glioma cells. J Pharm Pharmacol 64:120–127

    CAS  PubMed  Google Scholar 

  • Zhang Y, Kim MS, Jia B et al (2017a) Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature 548:52–57

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X-X, Yin L-K, Hao X-Z et al (2017b) Imaging the transformation of ipsilateral internal capsule following focal cerebral ischemia in rat by diffusion kurtosis imaging. J Stroke Cerebrovasc Dis 26:42–48

    PubMed  Google Scholar 

  • Zhang H, Sun X, Xie Y et al (2018a) Isosteviol sodium inhibits astrogliosis after cerebral ischemia/reperfusion injury in rats. Biol Pharm Bull 41:575–584

    CAS  PubMed  Google Scholar 

  • Zhang G, Chen L, Guo X et al (2018b) Comparative analysis of microRNA expression profiles of exosomes derived from normal and hypoxic preconditioning human neural stem cells by next generation sequencing. J Biomed Nanotechnol 14:1075–1089

    CAS  PubMed  Google Scholar 

  • Zhang H, Fang X, Huang D et al (2018c) Erythropoietin signaling increases neurogenesis and oligodendrogenesis of endogenous neural stem cells following spinal cord injury both in vivo and in vitro. Mol Med Rep 17(1):264–272

    CAS  PubMed  Google Scholar 

  • Zhang Y, Chopp M, Li C et al (2019) Exosomes derived from ischemic cerebral endothelial cells promote axonal growth. Stroke 50:A57–A57

    Google Scholar 

  • Zhao T, Zhang C, Liu Z et al (2008) Hypoxia-driven proliferation of embryonic neural stem/progenitor cells—role of hypoxia-inducible transcription factor-1alpha. FEBS J 275:1824–1834

    CAS  PubMed  Google Scholar 

  • Zhao Y, Luo P, Guo Q et al (2012) Interactions between SIRT1 and MAPK/ERK regulate neuronal apoptosis induced by traumatic brain injury in vitro and in vivo. Exp Neurol 237:489–498

    CAS  PubMed  Google Scholar 

  • Zheng Y, Song T, Zhang L et al (2018) Immunomodulatory effects of T helper 17 cells and regulatory T cells on cerebral ischemia. J Biol Regul Homeost Agents 32:29–35

    CAS  PubMed  Google Scholar 

  • Zhou Z, Dun L, Wei B et al (2020) Musk ketone induces neural stem cell proliferation and differentiation in cerebral ischemia via activation of the PI3K/Akt signaling pathway. Neuroscience 435:1–9

    CAS  PubMed  Google Scholar 

  • Zhu J, Coyne CB, Sarkar SN (2011) PKC alpha regulates Sendai virus-mediated interferon induction through HDAC6 and β-catenin. EMBO J 30:4838–4849

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu X, Yan J, Bregere C et al (2019) RBM3 promotes neurogenesis in a niche-dependent manner via IMP2-IGF2 signaling pathway after hypoxic-ischemic brain injury. Nat Commun 10:3983

    PubMed  PubMed Central  Google Scholar 

  • Zhu Z-H, Jia F, Ahmed W et al (2023) Neural stem cell-derived exosome as a nano-sized carrier for BDNF delivery to a rat model of ischemic stroke. Neural Regen Res 18:404–409

    PubMed  Google Scholar 

Download references

Acknowledgements

I would like to thank the research group for expertise and feedback, Ms. Wang for spiritual support, and Editage (www.editage.cn) for English language editing. Figure 1 and 2 were created with BioRender (BioRender.com).

Funding

This work was funded by the National Natural Science Foundation of China (No. 81971152) and the Natural Science Foundation of Liaoning Province (2019-ZD-0742).

Author information

Authors and Affiliations

  1. Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, China

    Yiting Fan, Jinshi Li & Bo Fang

Authors
  1. Yiting Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinshi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bo Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, BF; Investigation, YF; Writing original draft, YF; Writing review and editing, BF; Modification and review, JL. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Bo Fang.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Research Involving Human Participants and/or Animals

Not applicable.

Ethical Approval

Not applicable.

Informed Consent

Not applicable.

Consent for Publication

All authors provide consent for publication.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fan, Y., Li, J. & Fang, B. A Tale of Two: When Neural Stem Cells Encounter Hypoxia. Cell Mol Neurobiol 43, 1799–1816 (2023). https://doi.org/10.1007/s10571-022-01293-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-022-01293-6

Keywords

Search

Navigation