Priming of the Cells: Hypoxic Preconditioning for Stem Cell Therapy

Abstract

Objective: Stem cell-based therapies are promising in regenerative medicine for protecting and repairing damaged brain tissues after injury or in the context of chronic diseases. Hypoxia can induce physiological and pathological responses. A hypoxic insult might act as a double-edged sword, it induces cell death and brain damage, but on the other hand, sublethal hypoxia can trigger an adaptation response called hypoxic preconditioning or hypoxic tolerance that is of immense importance for the survival of cells and tissues.

Data sources: This review was based on articles published in PubMed databases up to August 16, 2017, with the following keywords: "stem cells," "hypoxic preconditioning," "ischemic preconditioning," and "cell transplantation."

Study selection: Original articles and critical reviews on the topics were selected.

Results: Hypoxic preconditioning has been investigated as a primary endogenous protective mechanism and possible treatment against ischemic injuries. Many cellular and molecular mechanisms underlying the protective effects of hypoxic preconditioning have been identified.

Conclusions: In cell transplantation therapy, hypoxic pretreatment of stem cells and neural progenitors markedly increases the survival and regenerative capabilities of these cells in the host environment, leading to enhanced therapeutic effects in various disease models. Regenerative treatments can mobilize endogenous stem cells for neurogenesis and angiogenesis in the adult brain. Furthermore, transplantation of stem cells/neural progenitors achieves therapeutic benefits via cell replacement and/or increased trophic support. Combinatorial approaches of cell-based therapy with additional strategies such as neuroprotective protocols, anti-inflammatory treatment, and rehabilitation therapy can significantly improve therapeutic benefits. In this review, we will discuss the recent progress regarding cell types and applications in regenerative medicine as well as future applications.

Figure 1

Human ESCs- and iPSCs-derived neuronal and glial cell therapeutics. This sketch shows the potential use of human ESCs- and iPSCs-derived neuronal and glial cells to treat the neurological disorders. ESCs: Embryonic stem cells; iPSCs: Induced pluripotent stem cells; TALEN: Transcription activator-like effector nucleases.

Figure 2

Mechanisms underlying the beneficial effects of hypoxic preconditioning. The hypoxic preconditioning strategy was designed to mimic and utilize endogenous protective mechanisms to promote neuroprotection, tissue regeneration, and brain function recovery. Hypoxic preconditioning directly induces HIF-1 upregulation that increases BDNF, SDF-1, VEGF, EPO, and many other genes which can stimulate neurogenesis, angiogenesis, vasodilatation, and increase cell survival. HIF-1 expression regulates antioxidants, survival signals, and other genes related to cell adhesion, polarization, migration, and anti-inflammatory responses. Partially adapted from a previous publication (Wei L, et al. Stem cell transplantation therapy for multifaceted therapeutic benefits after stroke. Prog Neurobiol 2017.). AhR: Aryl hydrocarbon receptor; AP-1: Activator protein 1; ARNT: AhR nuclear translocator; ASC: Adipose tissue-derived stromal stem cell; BDNF: Brain-derived neurotrophic factor; BMP-4: Bone morphogenetic protein 4; BMSC: Bone marrow-derived mesenchymal stem cell; Casp: Caspase; CBP: CREB-binding protein; CNS: Central nervous system; CREB: cAMP response element-binding protein; Cx43: Connexin 43; CSE: Cystathionine γ-lyase; CXCR-4: CXC chemokine receptor 4; Cyt c: Cytochrome c; Epac: Exchange protein directly activated by cAMP; EGF: Epidermal growth factor; EPC: Endothelial progenitor cell; EPO: Erythropoietin; ERK: Extracellular signal-regulated kinase; ESC: Embryonic stem cell; FAK: Focal adhesion kinase; FGF-2: Fibroblast growth factor-2; FoxO-3: Forkhead box O3; GDNF: Glial cell line-derived neurotrophic factor; G-6-PT: Glucose-6-phosphate transporter; GLUT-3: Glucose transporter isoform-3; GSK-3β: Glycogen synthase kinase-3 beta; H₂S: Hydrogen sulfide; Hes1: Hairy and enhancer of split 1; H/I: Hypoxia-ischemia; HIF-1α: Hypoxia-inducible factor-1 alpha; HRE: Hypoxia response element; Hsp: Heat shock protein; IL-10: Interleukin 10; JAK: Janus kinase; LIF: Leukemia inhibitory factor; LIFR: LIF receptor; miRNAs: microRNAs; MECP2: Methyl-CpG-binding protein 2; MIF: Migration inhibitory factor; MMP: Matrix metalloproteinase; MSCs: Mesenchymal stem cells; N2A: Neuro 2A; NCX-1: Sodium–calcium exchanger-1; NGN-1: Neurogenin-1; NOS: nitric oxide synthase; NSC: Neural stem cell; OCT-4: Octamer-binding transcription factor-4; OGD: Oxygen-glucose deprivation; OPC: Oligodendrocyte progenitor cell; PDAC: Pancreatic ductal adenocarcinoma; PDK: Pyruvate dehydrogenase kinase; PlGF: Placental growth factor; polyP: Polyphosphate; RasGAP: Ras-GTPase-activating protein; ROS: Reactive oxygen species; SCA-1: Stem cell antigen-1; SCAP: Stem cell from apical papilla; SCI: Spinal cord injury; SDF-1: Stromal-derived factor-1; STAT-3: Signal transducer and activator of transcription-3; SIRT-1: Silent-mating-type information regulation 2 homolog-1; SVP: Saphenous vein-derived pericyte; SVZ: Subventricular zone; TGFβ-1: Transforming growth factor β-1; TIMP-1: Tissue inhibitor of metalloproteinase; UCHSCs: Umbilical cord blood hematopoietic stem cells; UDPG: Uridine diphosphoglucose-glucose; UCP: Uncoupling protein; UVECs: Umbilical venous endothelial cells; VEGF: Vascular endothelial growth factor.