Table 1.
Effect of Hypoxia on Therapeutic Potential of Mesenchymal Stem Cells.
| Cell type | Hypoxia method | Oxygen levels and duration | Potential therapeutic application | Observations | References |
|---|---|---|---|---|---|
| Human OM-MSCs | Not mentioned | 3% (48 h) | Ischemic disease | Hypoxia generated OM-MSCs extracellular vesicles promote paracrine HIF-1α, VEGF signaling for angiogenesis, and enhanced proliferation and migration of human brain microvascular endothelial cells | Ge et al. 31 |
| Human OM-MSC | 92% N2 | 3% (48 h) | Intracerebral hemorrhage | Preconditioning of OM-MSC in hypoxia delays senescence and aids in the therapeutic efficacy of OM-MSCs in intracerebral hemorrhage model. microRNA-326 (miR-326) expression was significantly increased in the hypoxia OM-MSCs. | Liu et al. 32 |
| Human OM-MSC | Not mentioned | Below 0.5% O2 | Cerebral ischemia/reperfusion injury | OM-MSCs attenuated apoptosis and oxidative stress in ischemic stroke models and improved neurologic deficits in rats | He et al. 33 |
| Human OM-MSC | 94% N2 | 1% (48 h) | Cerebral ischemia/reperfusion injury | Hypoxia preconditioned OM-MSCs alleviate pyroptosis and apoptosis of microglial cells by HIF-1α activation | Huang et al. 34 |
| Human OM-MSC | Not mentioned | 3% | Parkinson’s disease | OM-MSCs differentiated into dopaminergic neurons at physiological oxygen level of 3%. Increase in β-tubulin and Tyrosine hydroxylase expression | Zhuo et al. 35 |
| Human OM-MSC | Not mentioned | 3% (48 h) | Cerebral ischemia | Hypoxia reduced gene expression at 5% serum of VEGF, GDNF, BDNF, and NGF and increased expression of Matrix metalloproteinase-2 and BDNF at 20% serum conditions | Yuan et al. 36 |
| Human BM-MSCs | Anaerobic chamber | 2% O2 (48 or 72 h) | Spinal cord injury repair | In vitro hypoxic pretreatment enhanced cell survival of transplanted BM-MSCs after spinal cord injury | Luo et al. 37 |
| Human BM-MSCs and porcine BM-MSCs | HypOxystation | 1%, 2%, or 5% for short term (48 h) and long term (10 days) | Acute respiratory distress syndrome | At 2% hypoxia, MSCs exhibited increased proliferation, self-renewal, and modulation of inflammatory genes. Potential to obtain MSCs with augmented function for therapeutic application | Antebi et al. 38 |
| Human BM-MSC | Hypoxic C-chamber | 1% (24 h) | BM-MSC stem cell therapy | Hypoxia induced HIF-1α enhanced the migration of BM-MSC through activation of matrix metalloproteinase-2 | Choi et al. 39 |
| Human BM-MSCs | 94% N2 | 5% O2 | BM-MSC stem cell therapy | Hypoxia increased proliferation and differentiation of BM-MSCs in both young and old healthy donors depending on age and culture conditions | Mohd et al. 40 |
| Human BM-MSC and Mouse BM-MSC | 94% N2 | 1% for 24 h | Upscaling MSC production for cell therapies | Hypoxia increased the size and number of neurospheres generated from BM-MSCs | Mung et al. 41 |
| Human BM-MSCs | Hypoxic C-Chamber connected to ProOx Model 21 controller | 2% O2 | Improving in vitro culture conditions for clinical application | Efficient expansion of BM-MSCs at 2% O2 compared with 20% O2. Increased cell proliferation and cellular metabolism | Dos Santos et al. 42 |
| Mouse BM-MSCs | 94% N2 Hypoxic cell incubator |
1% (48 h) | Spinal cord injury repair | Hypoxic preconditioning increased exosome production and the exosomes promoted functional recovery following SCI in mice by shuttling miR-216a-5p | Liu et al. 43 |
| Mouse BM-MSCs | ProOx-C-Chamber | 1.5% O2 (48 h) | Pulmonary fibrosis | Hypoxic preconditioning promoted cell proliferation, expansion, and reduced hydrogen peroxide induced cytotoxicity. Improved survival and lung function in bleomycin-induced pulmonary fibrotic mice was also observed | Lan et al. 44 |
| Mouse BM-MSCs | ProOx C-chamber system | 0.1%–0.3% O2 (24 h) | Ischemic stroke in mice | Intranasally delivered hypoxic preconditioned BM-MSCs showed enhanced homing to ischemic region and improved sensorimotor recovery in treated mice | Wei et al. 45 |
| Mouse BM-MSC | 94% N2 | 1% | Neovascularization and microvascular network remodeling | Enhanced cell migration and three-dimensional capillary-like structure formation in Matrigel. Increased expression of angiogenesis related markers | Annabi et al. 46 |
| Rat BM-MSCs | 90% N2 Incubator chamber | 5% O2 | Wound healing | Hypoxic pretreatment in combination with curcumin enhanced cell survival, mitochondrial fusion, and accelerated wound healing in a mice wound model | Wang et al. 47 |
| Rat BM-MSCs | 92% N2 | 3% O2 (24 h) | Spinal cord ischemia/reperfusion injury | Hypoxic preconditioning improved protective effects of BM-MSCs on neurological function, tissue damage, and inhibited apoptosis | Wang et al. 48 |
| Bovine BM-MSCs | 93% N2 HypOxystation | 2% O2
(1 week) |
Musculoskeletal tissue regeneration | Hypoxic preconditioning promoted BM-MSCs survival and extracellular matrix production in low oxygen and nutrient limited in vitro microenvironment | Peck et al. 49 |
| Human UC-MSCs | 94% N2 | 1% O2 (72 h) | Ischemia | Hypoxic stimulation increased production of microvesicles. These microvesicles promoted new vessel formation | Zhang et al. 50 |
| UC-MSCs | Various levels of N2 gas was used | 1.5%, 2.5%, and 5% (72 h) | Stem cell therapy | Hypoxia induced high metabolism rate at 1.5% and 2.5% O2 in UC-MSCs, reduced cell death, and increased cell proliferation | Lavrentieva et al. 51 |
OM-MSC: olfactory mucosa–mesenchymal stem cell; HIF-1α: hypoxia-inducible factor 1-alpha; VEGF: vascular endothelial growth factor; GDNF: glial-derived neurotrophic factor; BDNF: brain-derived neurotrophic factor; NGF: nerve growth factor; BM: bone marrow; SCI: spinal cord injury; UC: umbilical cord.