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

Abstract

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 hypoxic 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 was 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.

Malate-Based Biodegradable Scaffolds Activate Cellular Energetic Metabolism for Accelerated Wound Healing

“…Bone marrow mesenchymal stem cells (BMSCs) are a type of self-renewing and expandable stem cell with multidirectional differentiative potential and paracrine function and thus were widely used in different wound treatment. − The paracrine functions of BMSCs are responsible for improving wound healing, including promoting epidermal cell growth, angiogenesis, collagen deposition, suppressing inflammatory response, and closing wounds (Figure A) . Therefore, the paracrine levels of several relevant factors were measured, namely, TNF-α, IL-1β, CD31, VEGF, TGF-β1, and bFGF.…”

“…38−40 The paracrine functions of BMSCs are responsible for improving wound healing, including promoting epidermal cell growth, angiogenesis, collagen deposition, suppressing inflammatory response, and closing wounds (Figure 6A). 38 Therefore, the First, the gene expression levels of TNF-α, IL-1β, TGF-β1, CD31, VEGF, and bFGF by rBMSCs after being treated with MA solutions and the 10× diluted degradation products of PDoM (using POM-1.5 as the representative) for 24 h were studied by RT-qPCR. As shown in Figure 6B, the messenger ribonucleic acid (mRNA) expression levels of pro-inflammatory cytokines, including TNF-α and IL-1β, in the POM-1.5 and MA groups (except for MA2000 μM for TNF-α) were all significantly lower than that of the control and PLGA groups and comparable with that of POC group, indicating the favorable anti-inflammatory potential of PDoM.…”

3D-Printed Magnesium Peroxide-Incorporated Scaffolds with Sustained Oxygen Release and Enhanced Photothermal Performance for Osteosarcoma Multimodal Treatments

“…It has been well documented that HIF-1α can modulate several osteogenic protein expressions, including RUNX2 and OCN, thus affecting the differentiation of osteoblasts. 51 Altogether, the P10M scaffold can ameliorate local hypoxia and downregulate HIF-1α while promoting related osteogenic protein expression, ultimately facilitating osteogenic repair.…”

The establishment and development of wound repair discipline in China

“…One can build a suitable microenvironment for wound healing, one can load with stem cells and various healing promoting factors (growth factors, exosomes, etc. ), novel functional and intelligent biomimetic wound repair materials with anti-infective agents (21)(22)(23)(24)(25)(26)(27)(28)(29)(30).…”