ECM-regulation of autophagy: The yin and the yang of autophagy during wound healing

Sylakowski, Kyle; Wells, Alan

doi:10.1016/j.matbio.2020.12.006

Cited by 24 publications

(33 citation statements)

References 71 publications

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“…It has become evident that various cells and the associated extracellular matrix orchestrate this process. Indeed, the dynamic in uential nature of autophagy not only determines the proliferation and migration of epidermal cells in the wound bed but also directs the survival and fate of other cells as well as the transitions through the various phases of wound healing (44). Previous work has shown that epidermal stem cells and progenitor cells maintain their self-renewal capability through autophagy (45).…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells facilitate diabetic wound healing through the restoration of epidermal cell autophagy via the HIF-1α/TGF- β1 /SMAD pathway

Yang

Shi

Wang

et al. 2022

Preprint

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Background: The biological activity and regenerative medicine of bone marrow mesenchymal stem cells (BMSCs) have been focal topics in the broad fields of diabetic wound repair. However, the molecular mechanisms are still largely elusive for other cellular processes that are regulated during BMSC treatment. Our previous studies have shown that hypoxia is not only a typical pathological phenomenon of wounds but also exerts a vital regulatory effect on cellular bioactivity. In this study, the beneficial effects of hypoxia BMSCs on the cellular behaviors of epidermal cells and diabetic wound healing were investigated.Method: The viability and secretion ability of hypoxic BMSCs were detected. The autophagy, proliferation and migration of HaCaT cells cultured with hypoxic BMSCs-derived conditioned medium were assessed by estimating the expression of autophagy-related proteins, MTS, EdU proliferation and scratch assays. And the role of the SMAD signaling pathway during hypoxic BMSC-evoked HaCaT cell autophagy were explored through a series of in vitro gain- and loss-of-function experiments. Finally, the therapeutic effects of hypoxic BMSCs were evaluated using full-thickness cutaneous diabetic wound model.Results: First, we demonstrated that hypoxic conditions intensify HIF-1α-mediated TGF-β1 secretion by BMSCs. Then, the further data revealed that BMSC-derived TGF-β1 was responsible for the activation of epidermal cell autophagy, which contributed to the induction of epidermal cell proliferation and migration. Here, the SMAD signaling pathway was identified as downstream of BMSC-derived TGF-β1 to regulate HaCaT cell autophagy. Moreover, the administration of BMSCs to diabetic wounds increased epidermal autophagy and the rate of re-epithelialization, leading to accelerated healing, and these effects were significantly attenuated, accompanied by the downregulation of Smad2 phosphorylation levels due to TGF-β1 interference in BMSCs. Conclusion: In this report, we present evidence that uncovers a previously unidentified role of hypoxic BMSCs in regulating epidermal cell autophagy. The findings demonstrate that BMSC-based treatment by restoring epidermal cell autophagy could be an attractive therapeutic strategy for diabetic wounds and that the process is mediated by the HIF-1α/TGF-β1/SMAD pathway.

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Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells facilitate diabetic wound healing through the restoration of epidermal cell autophagy via the HIF-1α/TGF- β1 /SMAD pathway

Yang

Shi

Wang

et al. 2022

Preprint

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“…A growing body of research reveals the impact of autophagy on ECM function. For example, the realization that autophagy plays a key role in intervertebral disc and cartilage biology [240] and wound healing [241] provides some hints for future directions and a prospective translational impact for therapeutic application. Another intriguing observation is the link between syndecan 4, a member of the cell surface HSPGs, and autophagy as it relates to alveolar bone resorption in periodontitis [242].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth

Chen

Iozzo

2022

Open Biol.

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The extracellular matrix (ECM) exists as a dynamic network of biophysical and biochemical factors that maintain tissue homeostasis. Given its sensitivity to changes in the intra- and extracellular space, the plasticity of the ECM can be pathological in driving disease through aberrant matrix remodelling. In particular, cancer uses the matrix for its proliferation, angiogenesis, cellular reprogramming and metastatic spread. An emerging field of matrix biology focuses on proteoglycans that regulate autophagy, an intracellular process that plays both critical and contextual roles in cancer. Here, we review the most prominent autophagic modulators from the matrix and the current understanding of the cellular pathways and signalling cascades that mechanistically drive their autophagic function. We then critically assess how their autophagic functions influence tumorigenesis, emphasizing the complexities and stage-dependent nature of this relationship in cancer. We highlight novel emerging data on immunoglobulin-containing and proline-rich receptor-1, heparanase and thrombospondin 1 in autophagy and cancer. Finally, we further discuss the pro- and anti-autophagic modulators originating from the ECM, as well as how these proteoglycans and other matrix constituents specifically influence cancer progression.

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“…Wound healing is a complex, dynamic, and highly coordinated process of tissue protection involving immune cells, cytokines, chemokines, proteases, and growth factors that repair damaged tissue efficiently [ 23 , 24 , 25 ]. However, abnormal, prolonged or poor wound healing leads to infections, ulcers, hypertrophic scarring, and chronic wounds [ 28 , 29 ]. The cornea is a highly specialized, transparent, powerful refractive surface and a robust outer barrier protecting ocular tissue.…”

Section: Introductionmentioning

confidence: 99%

“…Novel therapeutic targets and approaches are needed to improve the corneal wound healing process to maintain sharp vision [ 16 , 21 , 22 , 36 , 37 ]. The ECM can regulate autophagy in normal wound healing mechanisms [ 28 ]. The corneal wound healing mechanism is a highly coordinated procedure associated with the cell death/necrosis/apoptosis, migration, proliferation, and differentiation of cells during the ECM remodeling process [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

Autophagy in Extracellular Matrix and Wound Healing Modulation in the Cornea

Kempuraj

Mohan

2022

Biomedicines

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Autophagy is a robust cellular mechanism for disposing of harmful molecules or recycling them to cells, which also regulates physiopathological processes in cornea. Dysregulated autophagy causes inefficient clearance of unwanted proteins and cellular debris, mitochondrial disorganization, defective inflammation, organ dysfunctions, cell death, and diseases. The cornea accounts for two-thirds of the refraction of light that occurs in the eyes, but is prone to trauma/injury and infection. The extracellular matrix (ECM) is a noncellular dynamic macromolecular network in corneal tissues comprised of collagens, proteoglycans, elastin, fibronectin, laminins, hyaluronan, and glycoproteins. The ECM undergoes remodeling by matrix-degrading enzymes and maintains corneal transparency. Autophagy plays an important role in the ECM and wound healing maintenance. Delayed/dysregulated autophagy impacts the ECM and wound healing, and can lead to corneal dysfunction. Stromal wound healing involves responses from the corneal epithelium, basement membrane, keratocytes, the ECM, and many cytokines and chemokines, including transforming growth factor beta-1 and platelet-derived growth factor. Mild corneal injuries self-repair, but greater injuries lead to corneal haze/scars/fibrosis and vision loss due to disruptions in the ECM, autophagy, and normal wound healing processes. Presently, the precise role of autophagy and ECM remodeling in corneal wound healing is elusive. This review discusses recent trends in autophagy and ECM modulation in the context of corneal wound healing and homeostasis.

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ECM-regulation of autophagy: The yin and the yang of autophagy during wound healing

Cited by 24 publications

References 71 publications

Bone marrow mesenchymal stem cells facilitate diabetic wound healing through the restoration of epidermal cell autophagy via the HIF-1α/TGF- β1 /SMAD pathway

Bone marrow mesenchymal stem cells facilitate diabetic wound healing through the restoration of epidermal cell autophagy via the HIF-1α/TGF- β1 /SMAD pathway

Extracellular matrix guidance of autophagy: a mechanism regulating cancer growth

Autophagy in Extracellular Matrix and Wound Healing Modulation in the Cornea

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