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Angiogenin derived from ABCB5+ mesenchymal stem cells improves diabetic wound via enhancing angiogenesis

ABSTRACT: Severe angiopathy has been postulated as a major driver for diabetes associated secondary complications. So far the knowledge on underlying mechanisms and thereon based therapeutic options to attenuate these pathologies are limited. Here we systematically administered ABCB5+ MSCs for the treatment of chronic non-healing diabetic wounds employing db/db mice, a type II diabetes model as their number markedly declined during diabetes. We found that administration of ABCB5+ MSCs markedly accelerates wound closure in diabetic db/db mice as opposed to the vehicle treated control group. Strikingly, administration of ABCB5+ MSCs at the edges of the diabetic wounds triggered considerable neoangiogenesis, most likely by the releasing a Ribonuclease angiogenin that was identified through secretome analysis of ABCB5+ MSCs. Interestingly, silencing of angiogenin in ABCB5+ MSCs significantly delayed wound closure in diabetic db/db mice indicating its key role in skin regeneration. Moreover, angiogenin also impacted the polarization of macrophages. The findings from this study will provide novel insight into the unique capacity of ABCB5+ MSCs to mount an adaptive response at the wound site with the delivery of angiogenic molecules holds significant promise for the therapy of non-healing diabetes foot ulcers, and other pathologies with impaired angiogenesis. The benefits for refined stem cell based therapies is virtually unlimited.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144169 | GEO | 2020/01/24

REPOSITORIES: GEO

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Angiogenin Released from ABCB5+ Stromal Precursors Improves Healing of Diabetic Wounds by Promoting Angiogenesis

Project description:Severe angiopathy is a major driver for diabetes associated secondary complications. Knowledge on underlying mechanisms essential for advanced therapies to attenuate these pathologies is limited. Injection of ABCB5+ stromal precursors (SPs) at the edge of non-healing diabetic wounds in a murine db/db model, closely mirroring human type II diabetes, profoundly accelerates wound closure. Strikingly, enhanced angiogenesis was substantially enforced by the release of the ribonuclease angiogenin from ABCB5+ SPs. This compensates for the profoundly reduced angiogenin expression in non-treated murine and human chronic diabetic wounds. Silencing of angiogenin in ABCB5+ SPs prior to injection significantly reduced angiogenesis, reduced numbers of M2 macrophages and delayed wound closure in diabetic db/db mice implying an unprecedented key role for angiogenin in tissue regeneration in diabetes. These data hold significant promise for further refining SPs-based therapies of non-healing diabetic foot ulcers and other pathologies with impaired angiogenesis.

2021-08-12 | GSE181881 | GEO

Newly defined ABCB5+ dermal mesenchymal stem cells promote healing of chronic iron overload wounds via secretion of interleukin-1 receptor antagonist

Project description:Here we report the beneficial effects of a newly identified dermal cell subpopulation expressing the ATP-binding cassette subfamily B member 5 (ABCB5) for the therapy of non-healing wounds. Local administration of dermal ABCB5+-derived MSCs attenuated macrophage-dominated inflammation and thereby accelerated healing of full-thickness excisional wounds in the iron overload mouse model mimicking the non-healing state of human venous leg ulcers. The observed beneficial effects were due to interleukin-1 receptor antagonist (IL-1RA) secreted by ABCB5+-derived MSCs, which dampened inflammation and shifted the prevalence of unrestrained pro-inflammatory M1 macrophages towards repair promoting anti-inflammatory M2 macrophages at the wound site. The beneficial anti-inflammatory effect of IL-1RA released from ABCB5+-derived MSCs on human wound macrophages was conserved in humanized NOD-scid IL2rγnull mice. In conclusion, human dermal ABCB5+ cells represent a novel, easy accessible and marker-enriched source of MSCs which holds substantial promise to successfully treat chronic non-healing wounds in humans.

2019-01-30 | GSE125829 | GEO

A global transcriptome analysis of skin wounds of diabetic mice (db/db) treated with miR-132 or control mimics

Project description:MiR-132 is one of the most upregulated miRNAs in human skin wounds at the inflammatory phase of healing. MiR-132 inhibits inflammation but promotes growth of epidermal keratinocytes, indicating that it may facilitate the inflammatory-proliferative phase transition during wound repair. Following this line of research, here we evaluated the therapeutic potential of miR-132 in chronic wound using mouse in vivo wound model. We performed a global transcriptome analysis of skin wounds of leptin receptor-deficient (db/db) mice treated with miR-132 or control mimics. Db/db mouse has been used as a type 2 diabetic model with impaired wound healing capacity.

2017-02-01 | GSE92409 | GEO

Gene expression profile at single cell level of skin cells isolated from db/db mice

Project description:The Janus liposozyme robustly eradicates infections and rapidly promotes wound closure and re-epithelialization on diabetic skin wound infected with methicillin-resistant S. aureus (MRSA). We used single cell RNA sequencing(scRNA-seq) to deep analyse local immune homeostasis manipulated by Janus on skin cells obtained from db/db mice .

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Il-22-Fc in cutaneous wound healing response

Project description:Diabetic foot ulcers (DFU) are one of the major complications in type II diabetes patients and can result in amputation and morbidity. Although multiple approaches are used clinically to help wound closure, many patients still lack adequate treatment. Here we show that IL-20 subfamily cytokines are upregulated during normal wound healing. While there is a redundant role for each individual cytokine in this subfamily in wound healing, mice deficient in IL-22R, the common receptor chain for IL-20, IL-22, and IL-24, display a significant delay in wound healing. Furthermore, IL-20, IL-22 and IL-24 are all able to promote wound healing in type II diabetic db/db mice. When compared to other growth factors such as VEGF and PDGF that accelerate wound healing in this model, IL-22 uniquely induced genes involved in reepithelialization, tissue remodeling and innate host defense mechanisms from wounded skin. Interestingly, IL-22 treatment showed superior efficacy compared to PDGF or VEGF in an infectious diabetic wound model. Taken together, our data suggest that IL-20 subfamily cytokines, particularly IL-20, IL-22, and IL-24, might provide therapeutic benefit for patients with DFU.

2017-03-08 | GSE80419 | GEO

HOXA3 expression in wound tissue

Project description:To investigate how HOXA3 expression in wound tissue alters gene expression to control selective recruitment of bone marrow-derived cell populations, we utilized murine whole genome expression arrays (MEEBO arrays) to identify differentially expressed genes in cutaneous wounds from db/db (diabetic) mice treated with either CMV-HOXA3 or control plasmid. In addition to unwounded control skin, we chose day 4 as the time point to harvest the wounds for RNA isolation, which represents the transition from inflammatory to proliferative phase of wound repair, and precedes the observed differences in BMDC mobilization and recruitment at day 7. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Disease State: cutaneous wound/control skin unwounded skin, wounded skin treated with control plasmid, wounded skin treated with HOXA3

2009-10-12 | E-GEOD-13324 | biostudies-arrayexpress

HOXA3 expression in wound tissue

2009-10-13 | GSE13324 | GEO

Alcaligenes faecalis corrects aberrant matrix metalloproteinase expression to promote re-epithelialization of diabetic wounds

Project description:Chronic wounds are a common and costly complication of diabetes, where multifactorial defects contribute to dysregulated skin repair, inflammation, tissue damage, and infection. We previously showed that aspects of the diabetic foot ulcer microbiota were correlated with poor healing outcomes, but many microbial species recovered remain uninvestigated with respect to wound healing. Here we focused onAlcaligenes faecalis, a Gram-negative bacterium that is frequently recovered from chronic wounds but rarely causes infection. Treatment of diabetic wounds withA. faecalisaccelerated healing during early stages. We investigated the underlying mechanisms and found thatA. faecalistreatment promotes re-epithelialization of diabetic keratinocytes, a process which is necessary for healing but deficient in chronic wounds. Overexpression of matrix metalloproteinases in diabetes contributes to failed epithelialization, and we found thatA. faecalistreatment balances this overexpression to allow proper healing. This work uncovers a mechanism of bacterial-driven wound repair and provides a foundation for the development of microbiota-based wound interventions.

2024-03-30 | GSE261418 | GEO

Gene expression profiling in murine mesenchymal stem cells treated with local anesthetics (ropivacaine)

Project description:Mesenchymal stem cells (MSCs) are recruited from the blood stream to tumors, healing wounds or sites of tissue injury by multiple growth factors and chemokines where they differentiate into e.g. fibroblasts or endothelial cells. Engrafted at the sites of tissue damage, they secrete growth factors and cytokines that facilitate healing. Inhibition of MSC proliferation by prolonged application of local anesthetics (commonly used after surgery) could delay wound closure and promote wound dehiscence. Culture-expanded bone-marrow-derived murine MSCs wewre treated in vitro with 100 uM ropivacaine for 24 hours (4 samples). Untreated MSCs served as controls.The collected cells were immediately frozen in liquid nitrogen and later used for RNA isolation and subsequent microarray hybridization. Gene-level analysis was performed. Exon-level analysis will be also performed.

2012-08-31 | E-GEOD-31827 | biostudies-arrayexpress

miRNA regulation in diabetes associated impaired wound healing

Project description:Circulating miRNAs constitute a novel class of disease biomarkers, which are altered in diabetes but the effect of diabetes associated inflammation as seen in chronic wounds is unknown. We here compared the miRNA pattern in diabetic patients in presence or absence of chronic wound with PAD. The clinical plasma samples were obtained from Heart and Diabetes centre, NRW and compared for plasma miRNA levels in 2 pools of 17 T2DM+PAD+Wound patients vs 2 pools from 20 T2DM controls

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