Newly defined ABCB5+ dermal mesenchymal stem cells promote healing of chronic iron overload wounds via secretion of interleukin-1 receptor antagonist
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE125829 | GEO | 2019/01/30
REPOSITORIES: GEO
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Project description: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.
2020-01-24 | GSE144169 | GEO
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
Project description:Acute kidney injury (AKI) is characterized by a rapid reduction in renal function and glomerular filtration rate (GFR). The broadly used anti-cancer chemotherapeutic agent cisplatin often induces AKI as an adverse drug side effect. Therapies targeted at the reversal of AKI and its potential progression to chronic kidney disease or end-stage renal disease are currently insufficiently effective. Mesenchymal stromal cells (MSC) possess diverse immunomodulatory properties that confer upon them significant therapeutic potential for the treatment of diverse inflammatory disorders. Human dermal MSCs expressing ATP-Binding Cassette member B5 (ABCB5) have shown therapeutic efficacy in clinical trials in chronic skin wounds or recessive dystrophic epidermolysis bullosa. In preclinical studies, ABCB5+ MSCs have also been shown to reverse metabolic reprogramming in polycystic kidney cells, suggesting a capacity for this cell subset to also improve organ function in kidney diseases. Here, we aimed to explore the therapeutic capacity of ABCB5+ MSCs to improve renal function in a preclinical rat model of cisplatin-induced AKI. First, ABCB5+ MSCs suppressed cisplatin-induced apoptosis of human conditionally-immortalized proximal tubular epithelial cells in vitro. Second, ABCB5+ MSCs inhibited the proliferation of either human or rat peripheral blood mononuclear cells. Third, ABCB5+ MSCs decreased TNF-α secretion after LPS stimulation in both human and rat macrophages. Fourth, clinical-grade ABCB5+ MSCs grafted intravenously and intraperitoneally to a cisplatin-induced AKI murine model exerted modulatory effects on mRNA expression patterns towards an anti-inflammatory and pro-regenerative state despite an apparent lack of amelioration of renal damage at physiologic, metabolic, and histologic levels. Our results demonstrate anti-inflammatory and pro-regenerative effects of clinical grade ABCB5+ MSCs in vitro and in vivo and suggest potential therapeutic utility of this cell population for treatment or prevention of cisplatin chemotherapy-induced tissue toxicity.
2024-01-04 | GSE223675 | GEO
Project description:Exudates of non-healing wounds contain drivers of pathogenicity. We utilized >800 exudates from non-healing and healing wounds of diverse etiologies, collected by three different methods, to develop a wound-specific, cell-based functional biomarker assay. Human dermal fibroblast proliferation served as readout to a) to differentiate between healing and non-healing wounds, b) follow the healing process of individual patients, and c) assess the effects of therapeutics for chronic wounds ex vivo. We observed a strong correlation between wound chronicity and inhibitory effects of individual exudates on fibroblast proliferation, with good diagnostic sensitivity (76-90%, depending on the sample collection method). Transition of a clinically non-healing to a healing phenotype restored fibroblast proliferation and extracellular matrix formation while reducing inflammatory cytokine production. Transcriptional analysis of fibroblasts exposed to ex vivo non-healing wound exudates revealed an induction of inflammatory cytokine- and chemokine pathways and the unfolded protein response, indicating that these changes may contribute to the pathology of non-healing wounds. Testing the wound therapeutics platelet derived growth factor and silver sulfadiazine yielded responses in line with clinical experience and indicate the usefulness of the assay to search for and profile new therapeutics.
2024-05-30 | GSE268639 | GEO
Project description:Exudates of non-healing wounds contain drivers of pathogenicity. We utilized >800 exudates from non-healing and healing wounds of diverse etiologies, collected by three different methods, to develop a wound-specific, cell-based functional biomarker assay. Human dermal fibroblast proliferation served as readout to a) to differentiate between healing and non-healing wounds, b) follow the healing process of individual patients, and c) assess the effects of therapeutics for chronic wounds ex vivo. We observed a strong correlation between wound chronicity and inhibitory effects of individual exudates on fibroblast proliferation, with good diagnostic sensitivity (76-90%, depending on the sample collection method). Transition of a clinically non-healing to a healing phenotype restored fibroblast proliferation and extracellular matrix formation while reducing inflammatory cytokine production. Transcriptional analysis of fibroblasts exposed to ex vivo non-healing wound exudates revealed an induction of inflammatory cytokine- and chemokine pathways and the unfolded protein response, indicating that these changes may contribute to the pathology of non-healing wounds. Testing the wound therapeutics platelet derived growth factor and silver sulfadiazine yielded responses in line with clinical experience and indicate the usefulness of the assay to search for and profile new therapeutics.
2024-05-30 | GSE268638 | GEO
Project description:In the present study, we demonstrate that hMSCs migrate toward human keratinocytes as well as toward conditioned medium from cultured human keratinocytes (KCM) indicating that the hMSCs can respond to signals from keratinocytes. Incubation of hMSCs with KCM induced dermal myofibroblast like differentiation characterized by expression of cytoskeletal markers vinculin and F-actin filaments with increased expression of alpha smooth muscle actin. We then examined the therapeutic efficacy of hMSCs in wound healing in two animal models representing normal and chronic wound healing. Accelerated wound healing, as determined by quantitative measurements of wound area, was observed when hMSCs and KCM exposed hMSCs (KCMSCs) were injected near the site of incisional/excisional wounds in nondiabetic athymic and NOD/SCID mice as compared with normal human fetal lung fibroblast WI38 cells or saline control induced wound healing. Experiment Overall Design: Keratinocyte conditioned media exposed MSCs(KCMSCs) were used in the experiment in triplicates as follows; Experiment Overall Design: KCM_1 Experiment Overall Design: KCM_2 Experiment Overall Design: KCM_3 Experiment Overall Design: Where as MSCs were exposed to Keratinocyte growth media for 30 days were used as a controls as follow; Experiment Overall Design: KGM_1 Experiment Overall Design: KGM_2 Experiment Overall Design: KGM_3 Experiment Overall Design: All the samples were analyzed.
2009-07-04 | E-GEOD-13073 | biostudies-arrayexpress
Project description:Human and murine skin wounding commonly result in fibrotic scarring but the murine wounding model Wound Induced Hair Neogenesis (WIHN) can frequently result in a regenerative repair response. Here we show in single cell RNA-seq comparisons of semi-regenerative and fibrotic WIHN wounds, increased expression of phagocytic/lysosomal genes in macrophages associated with predominance of fibrotic myofibroblasts in fibrotic wounds. Investigation revealed that macrophages in the late wound drive fibrosis by phagocytizing dermal Wnt inhibitor SFRP4 to establish persistent Wnt activity. In accordance, phagocytosis abrogation resulted in transient Wnt activity and a more regenerative healing. Phagocytosis of SFRP4 was integrin-mediated and dependent on the interaction of SFRP4 with the EDA splice variant of fibronectin. In the human skin condition Hidradenitis suppurativa, phagocytosis of SFRP4 by macrophages correlated with fibrotic wound repair. These results reveal that macrophages can modulate a key signaling pathway via phagocytosis to alter the skin wound healing fate.
2019-12-12 | GSE141814 | GEO
Project description:Ageing-related delays in wound healing are well-documented in both human and animal models. However, the mechanisms underlying this impairment in healing progression are not fully understood. In this study, we characterised ageing-associated changes to the structure and function of the skin in young and aged mice and investigated the cellular differences that impacted the progression of wound healing. Full-thickness wounds created on the dorsum of C57BL/6J young and aged mice were excised on Day 0, Day 3 and Day 7 post-wounding for analysis by immunohistochemistry, flow cytometry, RNA sequencing. Our data revealed that macrophages were significantly reduced in aged wounds in comparison to young. Functional transcriptomic analyses showed that macrophages from aged wounds exhibited significantly reduced expression of cell cycle, DNA replication, and repair pathway genes. Furthermore, we uncovered an elevated pro-inflammatory gene expression program in the aged macrophages linked to poor inflammation resolution and excessive tissue damage observed in aged wounds. Altogether, our work provides insights into how poorly healing aged wounds are phenotypically defined by the presence of macrophages with reduced proliferative capacity and an exacerbated inflammatory response, both of which are pathways that can be targeted to improve healing in the elderly.
2022-06-24 | GSE199763 | GEO
Project description:Bacterial infections of wounds are associated with poor healing and worse scarring. We sought to identify transcriptomic patterns associated with impaired healing of wounds infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) using a rabbit ear wound model. Wounds created on post-operative day (POD) 0 were infected on POD3, within the inflammatory phase of healing. On POD4 the infected wounds were harvested for microarray/transcriptome analysis. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12. On POD4 before antibiotic treatment, both wounds contained elevated transcripts that enriched predominantly into inflammation/infection-response pathways and functions characteristic of infiltrating leukocytes. But there were 5-fold more elevated transcripts in P.a.- than K.p.-infected wounds. Additionally, unique to P.a.-infected wounds, was a minor network of inflammation/infection-response molecules with predicted upstream regulation predominated by type I interferons. Also on POD4, Dnr-transcripts of both wounds were enriched into stress-response pathways such as EIF2 signaling. But there were 8-fold more Dnr-transcripts in P.a.- than K.p.-infected wounds, and many more of them enriched in the function, cell death, suggesting that resident dermal cells of P.a.-infected wounds failed to survive a more destructive P.a. infection. On POD6, following two days of antibiotic treatment, the biofilm-colonized wounds expressed magnitudes fewer inflammation and stress-response transcripts. However, a single regulatory network of P.a.-infected wounds was found to consist of Upr-transcripts enriching immune/infection-response functions predicted to be regulated by type I interferons, which was similar to the network unique to P.a.-infected wounds on POD4. On POD12, genes expressed by K.p.-infected wounds suggesting healing, while for P.a.-infected wounds they suggested stalled healing. The similarities and differences between the wound responses to these infections further define the molecular foundations of healing impaired by infections. Rabbit ear Wounds created on post-operative day (POD) 0 were infected with Klebsiella pneumoniae (K.p.) or Pseudomonas aeruginosa (P.a.) on POD3 and harvested on POD4 for RNA extraction. Other wounds with 24-hour infections were treated with topical antibiotic to promote biofilm formation and harvested on POD6 or POD12.
2014-01-01 | E-GEOD-51167 | biostudies-arrayexpress
Project description:Angiopoietin-like protein 4 (Angptl4) is a matricellular protein that associates with extracellular matrix proteins, mediating complex cell-cell, and cell-matrix interactions. It has been implicated in various inflammation-associated diseases, including wound healing, but very few reports describe a direct role for Angptl4 in the immune landscape of wound microenvironment. Here, we studied whether Angptl4 regulates the immune response during wound healing. Using single-cell RNA sequencing to examine the temporal changes in the immune cell landscape of excisional wounds from wild type and Angplt4-knockout (Angplt4-/-) mice revealed that Angptl4-/- wounds had a stalled inflammatory phase. Infiltrated neutrophils remained elevated in the Angptl4-/- wounds due to an impaired monocyte to macrophage differentiation needed for clearance. The impaired monocyte differentiation was also validated in wounds using multi-color flow cytometry. Pairwise comparisons of differentially expressed genes from wound-derived and bone-marrow derived macrophages demonstrated few differences, suggesting that Angptl4 has a confined regulome. We identified interferon activated protein 202B (ifi202b) to be consistently upregulated in Angptl4-/- macrophages. . Pathway analysis further confirmed that ifi202b significantly impacted multiple gene networks involved in the cell fate of monocytes and the functions of monocyte-derived macrophages. Taken altogether, we conclude that Angptl4 orchestrates the inflammatory state, innate immune landscape, and healing process in the wound microenvironment via its transcriptional regulation on ifi202b.
2022-03-02 | GSE186986 | GEO