Hypoxia-stimulated mesenchymal stem cell-derived exosomes loaded by adhesive hydrogel for effective angiogenic treatment of spinal cord injury

Mu, Jiafu; Li, Liming; Wu, Jiahe; Huang, Tianchen; Zhang, Yu; Cao, Jian; Ma, Teng; Chen, Jiachen; Zhang, Chenyang; Zhang, Xunqi; Ting-hao, LU; Kong, Xianglei; Sun, Jihong; J, Gao

doi:10.1039/d1bm01722e

Cited by 58 publications

(40 citation statements)

References 52 publications

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“…A significant rise in protein synthesis of EGF, fibroblast growth-factors, VEGF/VEGF receptors (VEGF-R), Ang-1, and angiopoietin receptor tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (Tie-1) were shown in grafted animals, 30 d after transplantation[ 106 ]. Inclusion in hydrogels that allow local release of EV with high angiogenic capacity has also been used for treatment of spinal-cord injuries[ 107 ]. One of the proteins that has been found to be over synthesized in MSC-derived EV under hypoxia, compared to those obtained in normoxia, is jagged-1 (JAG1).…”

Section: Therapeutic Potential Of Ev Derived From Msc Preconditioned ...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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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: Therapeutic Potential Of Ev Derived From Msc Preconditioned ...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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“…Previous studies have shown that exogenous hypoxic treatment prevents the degradation of HIF-1α and favors the accumulation of cellular HIF-1α in a time-dependent manner, followed by their integration into the exosomes. [57,58] Therefore, we hypothesized that hypoxic treatment might increase the content of HIF-1α in E-Exos, which could achieve self-presentation to elevate its endogenous level. To confirm the abundance of HIF-1α protein in E-Exos, the expression of HIF-1α in exosomes was analyzed under different induction conditions by using an ELISA kit (Figure S37a, Supporting Information), demonstrating that hypoxia and TNF-α/hypoxia stimulations induce massive aggregation of HIF-1α in E-Exos, supporting the idea that HIF-1α-enriched E-Exos contributes to endogenous HIF-1α accumulation in wound sites.…”

Section: Suppression Of Oxidative Stress Inflammation and Promotion O...mentioning

confidence: 99%

An Optimally Designed Engineering Exosome–Reductive COF Integrated Nanoagent for Synergistically Enhanced Diabetic Fester Wound Healing

Sun

Wang

et al. 2022

Small

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Oxidative stress and local overactive inflammation have been considered major obstacles in diabetic wound treatment. Although antiphlogistic tactics have been reported widely, they are also challenged by pathogen contamination and compromised angiogenesis. Herein, a versatile integrated nanoagent based on 2D reductive covalent organic frameworks coated with antibacterial immuno‐engineered exosome (PCOF@E‐Exo) is reported to achieve efficient and comprehensive combination therapy for diabetic wounds. The E‐Exo is collected from TNF‐α‐treated mesenchymal stem cells (MSCs) under hypoxia and encapsulated cationic antimicrobial carbon dots (CDs). This integrated nanoagent not only significantly scavenges reactive oxygen species and induces anti‐inflammatory M2 macrophage polarization, but also stabilizes hypoxia‐inducible factor‐1α (HIF‐1α). More importantly, the PCOF@E‐Exo exhibits intriguing bactericide capabilities toward Gram‐negative, Gram‐positive, and drug‐resistant bacteria, showing favorable intracellular bacterial destruction and biofilm permeation. In vivo results demonstrate that the synergetic impact of suppressing oxidative injury and tissue inflammation, promoting angiogenesis and eradicating bacterial infection, could significantly accelerate the infected diabetic fester wound healing with better therapeutic benefits than monotherapy or individual antibiotics. The proposed strategy can inspire further research to design more delicate platforms using the combination of immunotherapy with other therapeutic methods for more efficient ulcerated diabetic wounds treatments.

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“…Fortunately, MSC-derived exosomes (MSC-EXOs) secreted by MSCs have similar therapeutic benefits for immune modulation when injected into acute SCI lesions 16–20 . Previous studies have shown that MSC-EXOs immobilized in a peptide-modified adhesive hydrogel transplanted into an SCI lesion during the acute phase could mitigate the SCI microenvironment and promote functional recovery 21,22 . However, the retention time of MSC-EXOs in spinal tissue might not be long enough for them to exhibit their optimal therapeutic effects.…”

Section: Introductionmentioning

confidence: 99%

“…[9] Previous studies have shown that the transplantation of MSC-EXO immobilized in a peptide-modified adhesive hydrogel into an SCI lesion during the acute phase could mitigate the SCI microenvironment and promote functional recovery. [10] However, the retention time of MSC-EXO in the spinal tissue might not be long enough to exhibit their optimal therapeutic effects. The neuroinflammation and neuronal apoptosis caused by SCI could continue for a couple of weeks or even longer, [11] but MSC-EXO could not be continuously delivered into the lesion of SCI by these methods.…”

Section: Introductionmentioning

confidence: 99%

Porous microneedle patch with sustained exosome delivery repairs severe spinal cord injury

Fang

Wang

Guan

et al. 2022

Preprint

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1.AbstractThe transplantation of mesenchymal stem cells-derived exosomes (MSC-EXO) has been suggested as an efficacious treatment to suppress SCI-triggered neuroinflammation. However, an ethically acceptable method to continuously deliver MSC-EXO into the acute spinal lesion without damaging spared tissues/axons has never been achieved. In this study, we fabricated a device that consists of a patch containing MSC and microneedle array (MN-MSC patch) to treat severe SCI. When topically applied to the acute spinal lesion beneath spinal dura, the soft microneedle (MN) array with good mechanical strength avoids damages to the spared spinal tissues and the porous microstructure of MN facilitates highly efficient MSC-EXO delivery. With the capacity to sustainedly deliver MSC-EXO, the MN-MSC patch was evaluated in a contusive rat SCI model and showed that the MSCs encapsulated in the patch could survive for at least 7 days, which covers the optimal time window for down-regulating SCI-triggered neuroinflammation. As a result, the MN-MSC patch treatment leads to reduced cavity and scar tissue formation, angiogenesis, and the survival of spared tissues/axons. Remarkably, the rats treated by this method achieved superior muscle control and exhibited robust hindlimb locomotion functional recovery. Conclusively, the MN-MSC patch device proposed here breaks through the current dilemma from the contradiction between treatment efficacy and ethical issues in treating acute SCI.

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Hypoxia-stimulated mesenchymal stem cell-derived exosomes loaded by adhesive hydrogel for effective angiogenic treatment of spinal cord injury

Abstract: Implantation of hypoxia-stimulated mesenchymal stem cell-derived exosome encapsulated in an adhesive hydrogel induced pro-angiogenic spinal cord repair through transporting HIF-1α and upregulating vascular endothelial growth factor expression in recipient endothelial cells.

Cited by 58 publications

References 52 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

An Optimally Designed Engineering Exosome–Reductive COF Integrated Nanoagent for Synergistically Enhanced Diabetic Fester Wound Healing

Porous microneedle patch with sustained exosome delivery repairs severe spinal cord injury

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