Cathepsin K inhibitor and hUMSC-EVs synergistically promote diabetic wound healing by suppressing ferroptosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Rui Guo
PROVIDER: PXD067444 | iProX | Mon Aug 18 00:00:00 BST 2025
REPOSITORIES: iProX
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Project description:Impaired healing of diabetic wounds causes significant morbidity and mortality. This study aimed to identify novel mechanisms of diabetic wound healing defects and test a therapeutic intervention using diabetic mouse and pig models. We found Smad7 transgene expression in mouse epidermis promoting wound healing in diabetic db/db mice, with reductions in obesity and blood glucose. To isolate effects of Smad7 on wounds, we created a Smad7-based biologic (Tat-PYC-Smad7) that penetrates wound cells. Topical application of Tat-PYC-Smad7 to diabetic pig and mouse wounds accelerated healing compared to controls. RNAseq analysis of mouse wound samples showed reduced TGFβ/NFκB signaling, leading to faster re-epithelialization and better extracellular matrix remodeling. Tat-PYC-Smad7 also attenuated neutrophil degranulation and NETosis by blocking histone 3 citrullination and inhibiting myeloperoxidase activities. Our study reveals that Tat-PYC-Smad7 promotes diabetic wound healing by targeting keratinocytes and neutrophils, providing insight into cellular mechanisms of diabetic wound healing defects targetable by Smad7-based therapy.
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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
Project description:Diabetes is a major growing public health concern, but the impact on cellular impairments in chronic wounds remains incompletely understood. Fibroblasts, key players in all phases of wound healing, are particularly responsive to mechanotransduction. Here, we characterize fibroblast heterogeneity in genetically induced and pathophysiological diabetic murine wounding models across all wound healing phases. Full-thickness excisional wounds were created on the dorsum of C57BL/6 non-diabetic wild-type (WT) mice (N-DB), WT-mice fed a high-fat diet to create pathophysiologic diabetes (P-DB), and leptin-receptor-deficient mice, a genetically induced diabetic model (G-DB). Tissue was submitted for single-cell RNA sequencing at postoperative days (PODs) 0, 2, 7 and 30. Both G-DB and P-DB significantly impaired wound healing compared to N-DB. N-DB expressed distinct myeloid-like Cd14+/C1qa+ angiogenic fibroblasts at PODs 2, and 7. Mechanotransduction pathways FAK and MAPK were consistently upregulated in N-DB fibroblasts and depleted in both diabetic models. G-DB upregulated WNT-activated Dpp4+ fibrotic fibroblasts at POD7 compared to N-DB. Thus, mechanotransduction pathways are present in physiologically healing fibroblasts and are selectively depleted in both pathophysiologic and genetically induced diabetes. In genetically induced diabetes, overactivation of canonical and non-canonical WNT pathways overwhelms cells and impairs healing processes. Transcriptomic insights into these mechanotransducive perturbations may lead to new therapies for diabetic wound repair.
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Project description:Wound healing is a multi-step process to rapidly restore barrier function. This process is often impaired in diabetic patients resulting in chronic wounds and amputation. We previously found that paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway via topical administration of the BRAF inhibitor vemurafenib accelerates wound healing by activating keratinocyte proliferation and reepithelialization pathways in healthy mice. Herein, we investigated whether this wound healing acceleration also occurs in impaired diabetic wounds and found that topical vemurafenib not only improves wound healing in a murine diabetic wound model, but unexpectedly promotes hair follicle regeneration. Neogenic hair follicles expressing Sox-9, CD34 and K15 were found in wounds of diabetic and non-diabetic mice, and their formation can be prevented by blocking downstream MEK signaling. Thus, topically applied BRAF inhibitors may accelerate wound healing, and promote the restoration of improved skin architecture in both normal and impaired wounds.
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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.
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Project description:Impaired healing of diabetic wounds causes significant morbidity and mortality. This study aimed to identify novel mechanisms of diabetic wound healing defects and test a therapeutic intervention using diabetic mouse and pig models. We found Smad7 transgene expression in mouse epidermis promoting wound healing in diabetic dbdb mice, with reductions in obesity and blood glucose. To isolate effects of Smad7 on wounds, we created a Smad7-based biologic (Tat-PYC-Smad7) that penetrates wound cells. Topical application of Tat-PYC-Smad7 to diabetic pig and mouse wounds accelerated healing compared to controls. RNAseq analysis of mouse wound samples showed reduced TGF/NFB signaling, leading to faster re-epithelialization and better extracellular matrix remodeling. Tat-PYC-Smad7 also attenuated neutrophil degranulation and NETosis by blocking histone 3 citrullination and inhibiting myeloperoxidase activities. Our study reveals that Tat-PYC-Smad7 promotes diabetic wound healing by targeting keratinocytes and neutrophils, providing insight into cellular mechanisms of diabetic wound healing defects targetable by Smad7-based therapy.
2024-08-07 | MSV000095545 | MassIVE
Project description:This a model from the article:
Modeling the effects of treating diabetic wounds with engineered skin
substitutes.
Waugh HV, Sherratt JA. Wound Repair Regen
2007 Jul-Aug;15(4):556-65 17650100
,
Abstract:
In this paper, a novel mathematical model of wound healing in both normal and
diabetic cases is presented, focusing upon the effects of adding two currently
available commercial engineered skin substitute therapies to the wound
(Apligraf) and Dermagraft). Our work extends a previously developed model, which
considers inflammatory and repair macrophage dynamics in normal and diabetic
wound healing. Here, we extend the model to include equations for
platelet-derived growth factor concentration, fibroblast density, collagen
density, and hyaluronan concentration. This enables us to examine the variation
of these components in both normal and diabetic wound healing cases, and to
model the treatment protocols of these therapies. Within the context of our
model, we find that the key component to successful healing in diabetic wounds
is hyaluronan and that the therapies work by increasing the amount of hyaluronan
available in the wound environment. The time-to-healing results correlate with
those observed in clinical trials and the model goes some way to establishing an
understanding of why diabetic wounds do not heal, and how these treatments
affect the diabetic wound environment to promote wound closure.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Waugh HV, Sherratt JA. (2007) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230102 | BioModels
Project description:This a model from the article:
Modeling the effects of treating diabetic wounds with engineered skin
substitutes.
Waugh HV, Sherratt JA. Wound Repair Regen
2007 Jul-Aug;15(4):556-65 17650100
,
Abstract:
In this paper, a novel mathematical model of wound healing in both normal and
diabetic cases is presented, focusing upon the effects of adding two currently
available commercial engineered skin substitute therapies to the wound
(Apligraf) and Dermagraft). Our work extends a previously developed model, which
considers inflammatory and repair macrophage dynamics in normal and diabetic
wound healing. Here, we extend the model to include equations for
platelet-derived growth factor concentration, fibroblast density, collagen
density, and hyaluronan concentration. This enables us to examine the variation
of these components in both normal and diabetic wound healing cases, and to
model the treatment protocols of these therapies. Within the context of our
model, we find that the key component to successful healing in diabetic wounds
is hyaluronan and that the therapies work by increasing the amount of hyaluronan
available in the wound environment. The time-to-healing results correlate with
those observed in clinical trials and the model goes some way to establishing an
understanding of why diabetic wounds do not heal, and how these treatments
affect the diabetic wound environment to promote wound closure.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Waugh HV, Sherratt JA. (2007) - version=1.0
The original CellML model was created by:
Catherine Lloyd
c.lloyd@auckland.ac.nz
The University of Auckland
This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team.
To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication
for more information.
In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not..
To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.
2005-01-01 | MODEL1006230003 | BioModels