Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling

DeFrates, Kelsey G.; Franco, Daniela; Heber‐Katz, Ellen; Messersmith, Phillip B.

doi:10.1016/j.biomaterials.2020.120646

Cited by 25 publications

(22 citation statements)

References 342 publications

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“…These genes are involved in adaptation of cells to hypoxic conditions. They affect different physiological processes including metabolism, angiogenesis, inflammatory response, cell differentiation, migration, and apoptosis[ 57 ]. In order to present an overview of the various functions of genes regulated by HIF1α and HIF2α, we have analyzed the information contained in Qiagen Ingenuity Pathway Analysis (Qiagen IPA) web-based software application ( )[ 58 ].…”

Section: Role Of Hypoxia-inducible Factor In Adaptation To Hypoxia An...mentioning

confidence: 99%

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Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Pulido-Escribano¹,

Torrecillas-Baena²,

Camacho-Cardeñosa³

et al. 2022

WJSC

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The use of mesenchymal stem-cells (MSC) in cell therapy has received considerable attention because of their properties. These properties include high expansion and differentiation in vitro , low immunogenicity, and modulation of biological processes, such as inflammation, angiogenesis and hematopoiesis. Curiously, the regenerative effect of MSC is partly due to their paracrine activity. This has prompted numerous studies, to investigate the therapeutic potential of their secretome in general, and specifically their extracellular vesicles (EV). The latter contain proteins, lipids, nucleic acids, and other metabolites, which can cause physiological changes when released into recipient cells. Interestingly, contents of EV can be modulated by preconditioning MSC under different culture conditions. Among them, exposure to hypoxia stands out; these cells respond by activating hypoxia-inducible factor (HIF) at low O 2 concentrations. HIF has direct and indirect pleiotropic effects, modulating expression of hundreds of genes involved in processes such as inflammation, migration, proliferation, differentiation, angiogenesis, metabolism, and cell apoptosis. Expression of these genes is reflected in the contents of secreted EV. Interestingly, numerous studies show that MSC-derived EV conditioned under hypoxia have a higher regenerative capacity than those obtained under normoxia. In this review, we show the implications of hypoxia responses in relation to tissue regeneration. In addition, hypoxia preconditioning of MSC is being evaluated as a very attractive strategy for isolation of EV, with a high potential for clinical use in regenerative medicine that can be applied to different pathologies.

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Section: Role Of Hypoxia-inducible Factor In Adaptation To Hypoxia An...mentioning

confidence: 99%

“…Among the functions of genes regulated by HIF1A and HIF2A are those related to glucose metabolism, vessel formation, inflammatory response, cell proliferation, cell migration, and apoptosis. Interestingly, they play relevant roles in tissue regeneration[ 57 ].…”

Section: Role Of Hypoxia-inducible Factor In Adaptation To Hypoxia An...mentioning

confidence: 99%

Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Pulido-Escribano¹,

Torrecillas-Baena²,

Camacho-Cardeñosa³

et al. 2022

WJSC

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“…S2A). The level of HIF-1α is influenced by protein synthesis and protein degradation, and the degradation of HIF-1α is mainly affected by oxygen levels [ 41 ]. To explore whether hsEVs affect HIF-1α expression through protein synthesis and degradation, ADSCs were treated with hsEVs and MG132 as indicated.…”

Section: Resultsmentioning

confidence: 99%

Small extracellular vesicles of hypoxic endothelial cells regulate the therapeutic potential of adipose-derived mesenchymal stem cells via miR-486-5p/PTEN in a limb ischemia model

et al. 2022

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Background Patients with critical limb ischemia (CLI) are at great risk of major amputation and cardiovascular events. Adipose-derived mesenchymal stem cell (ADSC) therapy is a promising therapeutic strategy for CLI, but the poor engraftment and insufficient angiogenic ability of ADSCs limit their regenerative potential. Herein, we explored the potential of human umbilical vein endothelial cells (HUVECs)-derived small extracellular vesicles (sEVs) for enhancing the therapeutic efficacy of ADSCs in CLI. Results sEVs derived from hypoxic HUVECs enhanced the resistance of ADSCs to reactive oxygen species (ROS) and further improved the proangiogenic ability of ADSCs in vitro. We found that the hypoxic environment altered the composition of sEVs from HUVECs and that hypoxia increased the level of miR-486-5p in sEVs. Compared to normoxic sEVs (nsEVs), hypoxic sEVs (hsEVs) of HUVECs significantly downregulated the phosphatase and tensin homolog (PTEN) via direct targeting of miR-486-5p, therefore activating the AKT/MTOR/HIF-1α pathway and influencing the survival and pro-angiogenesis ability of ADSCs. In a hindlimb ischemia model, we discovered that hsEVs-primed ADSCs exhibited superior cell engraftment, and resulted in better angiogenesis and tissue repair. Conclusion hsEVs could be used as a therapeutic booster to improve the curative potential of ADSCs in a limb ischemia model. This finding offers new insight for CLI treatment. Graphical Abstract

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“…Upon establishing anesthesia, mice were placed into the microCT FX (Perkin Elmer; ref 78) tray with the isoflurane nose cone. 3D images were collected and rendered with a voltage of 90kV a CT current of 160 μA and a live current of 80 μA for 17 seconds time for a total dose of 11milliGY (78)(79). This constitutes the pre-intervention baseline.…”

Section: Microct Scanningmentioning

confidence: 99%

Prolyl-hydroxylase inhibitor-induced regeneration of alveolar bone and soft tissue in a mouse model of ligature-induced periodontitis

Zebrowitz

Kajikawa

Bedelbaeva

et al. 2021

Preprint

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Bone injuries and fractures reliably heal through a process of regeneration with restoration to original structure and function when the gap between adjacent sides of a fracture site is small. However, when there is significant volumetric loss of bone, bone regeneration usually does not occur.In the present studies, we explore a particular case of volumetric bone loss in a mouse model of human periodontal disease (PD) in which alveolar bone surrounding teeth is permanently lost and not replaced. This model employs the placement a ligature around the upper second molar which leads to inflammation and bone breakdown and faithfully replicates the bacterially-induced inflammatory etiology of human PD to induce bone degeneration. After 10 days, the ligature is removed and the mice are treated with a timed-release formulation of a small molecule inhibitor of prolylhydroxylases (PHDi; 1,4-DPCA) previously shown to induce epimorphic regeneration of soft tissue in non-regenerating mice. This PHDi induces high expression of HIF-1α and the regenerative response is completely blocked by siHIF1a. Here, we observe that timed-release 1,4-DPCA rapidly and completely restores bone and soft tissue with normal anatomic fidelity and with increased stem cell markers due to stem cell migration into the site and/or de-differentiation of local tissue, PDL cell proliferation, and increased vascularization. In-vitro studies using gingival tissue show that 1,4-DPCA indeed induces de-differentiation and the expression of stem cell markers but does not exclude the role of migrating stem cells.

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Unlocking mammalian regeneration through hypoxia inducible factor one alpha signaling

Cited by 25 publications

References 342 publications

Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Small extracellular vesicles of hypoxic endothelial cells regulate the therapeutic potential of adipose-derived mesenchymal stem cells via miR-486-5p/PTEN in a limb ischemia model

Prolyl-hydroxylase inhibitor-induced regeneration of alveolar bone and soft tissue in a mouse model of ligature-induced periodontitis

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