Invited Response on: Letter to the Editor on “Extracellular Vesicles From a Three-Dimensional Culture of Perivascular Cells Accelerate Skin Wound healing in a Rat”

Engineered skin that can facilitate tissue repair has been a great advance in the field of wound healing. A well-designed dressing material together with active biological cues such as cells or growth factors can overcome the limitation of using auto-grafts from patients. Recently, many studies showed that human adipose-derived stem cells (hASCs) can be used to promote wound healing and skin tissue engineering. hASCs have already been widely applied for clinical trials. hASCs can be harvested abundantly because they can be easily isolated from fat tissue known as the stromal vascular fraction (SVF). On the other hand, increasing studies have proven that cells from spheroids can better simulate the biological microenvironment and can enhance the expression of stemness markers. However, a three-dimensional (3D) scaffold that can harbor implanted cells and can serve as a skin-repaired substitute still suffers from deficiency. In this study, we applied a gelatin/microbial transglutaminase (mTG) hydrogel to encapsulate hASC spheroids to evaluate the performance of 3D cells on skin wound healing. The results showed that the hydrogel is not toxic to the wound and that cell spheroids have significantly improved wound healing compared to cell suspension encapsulated in the hydrogel. Additionally, a hydrogel with cell spheroids was much more effective than other groups in angiogenesis since the cell spheroid has the possibility of cell–cell signaling to promote vascular generation.

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Extracellular Vesicles from Adipose-Derived Mesenchymal Stem/Stromal Cells Accelerate Migration and Activate AKT Pathway in Human Keratinocytes and Fibroblasts Independently of miR-205 Activity

Stem Cells International ◽

10.1155/2017/9841035 ◽

2017 ◽

Vol 2017 ◽

pp. 1-14 ◽

Cited By ~ 20

Author(s):

Andrea da Fonseca Ferreira ◽

Pricila da Silva Cunha ◽

Virgínia Mendes Carregal ◽

Priscila de Cássia da Silva ◽

Marcelo Coutinho de Miranda ◽

...

Keyword(s):

Wound Healing ◽

Extracellular Vesicles ◽

Stromal Cells ◽

Average Diameter ◽

Skin Wound ◽

Akt Pathway ◽

Skin Wound Healing ◽

Akt Phosphorylation ◽

Akt Activation

Mesenchymal stem/stromal cells (MSCs) are promising tools in cell therapy. They secrete extracellular vesicles (EVs) that carry different classes of molecules that can promote skin repair, but the mechanisms are poorly understood. Skin wound healing is a complex process that requires the activity of several signaling pathways and cell types, including keratinocytes and fibroblasts. In this study, we explored whether adipose tissue MSC-derived EVs could accelerate migration and proliferation of keratinocytes and fibroblasts, activate the AKT pathway, and promote wound healing in vivo. Furthermore, we evaluated if EV effects are miR-205 dependent. We found that MSC EVs had an average diameter of 135 nm. Keratinocytes and fibroblasts exposed to EVs exhibited higher levels of proliferation, migration, and AKT activation. Topical administration of EVs accelerated skin wound closure. Knockdown of miR-205 decreased AKT phosphorylation in fibroblasts and keratinocytes, whereas migration was decreased only in keratinocytes. Moreover, knockdown of miR-205 failed to inhibit AKT phosphorylation in fibroblasts and keratinocytes exposed to EVs. About the mechanism of EV effects, we found that incubation with EVs prevented inhibition of AKT activation by miR-205 knockdown, suggesting that EVs activate AKT independently of miR-205. In conclusion, we demonstrated that EVs are a promising tool for wound healing.

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microRNA‐106b derived from endothelial cell–secreted extracellular vesicles prevents skin wound healing by inhibiting JMJD3 and RIPK3

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16037 ◽

2021 ◽

Author(s):

Lin Qi ◽

Yufeng Lu ◽

Zhaolin Wang ◽

Guiyun Zhang

Keyword(s):

Wound Healing ◽

Endothelial Cell ◽

Extracellular Vesicles ◽

Skin Wound ◽

Skin Wound Healing

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Three-Dimensional (3D) Fibronectin Nano-Array Presented on Fibrin Matrix Accelerates Mice Skin Wound Healing

10.1101/2020.05.04.077891 ◽

2020 ◽

Author(s):

Carlos Poblete Jara ◽

Ou Wang ◽

Thais Paulino do Prado ◽

Ayman Ismail ◽

Frank Marco Fabian ◽

...

Keyword(s):

Wound Healing ◽

Umbilical Vein ◽

Human Fibroblasts ◽

Three Dimensional ◽

Fibrin Clot ◽

Skin Wound ◽

Molar Ratio ◽

Skin Wound Healing ◽

Fibrin Matrix ◽

Highly Active

AbstractPlasma fibrinogen (F1) and fibronectin (pFN) polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound healing. About 90% of plasma F1 has a homodimeric pair of γ chains (γγF1) and 10% has a heterodimeric pair of γ and more acidic γ’ chains (γγ’F1). We have synthesized a novel fibrin matrix exclusively from a 1:1 (molar ratio) complex of γγ’F1 and pFN in the presence of highly active thrombin and recombinant Factor XIII (rFXIIIa). In this matrix, the fibrin nanofibers were wrapped with periodic 200-300 nm wide pFN nanobands (termed γγ’F1:pFN fibrin). In contrast, fibrin made from 1:1 mixture of γγF1 and pFN formed a sporadic distribution of “pFN droplets” (termed γγF1 +pFN fibrin). The γγ’F1:pFN fibrin enhanced the adhesion of primary human umbilical vein endothelium cells (HUVECs) relative to the γγF1+FN fibrin. Three dimensional (3D) culturing showed that the γγ’F1:pFN complex fibrin matrix enhanced the proliferation of both HUVECs and primary human fibroblasts. HUVECs in the 3D γγ’F1:pFN fibrin exhibited a starkly enhanced vascular morphogenesis while an apoptotic growth profile was observed in the γγF1 +pFN fibrin. Relative to γγF1 +pFN fibrin, mouse dermal wounds that were sealed by γγ’F1:pFN fibrin exhibited accelerated and enhanced healing. This study suggests that a 3D pFN nano-array presented on a fibrin matrix can promote wound healing.

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Bone marrow-derived mesenchymal stem cells and extracellular vesicles enriched collagen chitosan scaffold in skin wound healing (a rat model)

Journal of Biomaterials Applications ◽

10.1177/0885328220963920 ◽

2020 ◽

pp. 088532822096392

Author(s):

Salma Abolgheit ◽

Sally Abdelkader ◽

Moustafa Aboushelib ◽

Enas Omar ◽

Radwa Mehanna

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Wound Healing ◽

Tensile Strength ◽

Mesenchymal Stem Cells ◽

Extracellular Vesicles ◽

Skin Wound ◽

Collagen Deposition ◽

Skin Wound Healing ◽

Chitosan Scaffolds

Background Over the past ten years, regenerative medicine has focused on the regeneration and the reconstruction of damaged, diseased, or lost tissues and organs. Skin, being the largest organ in the human body, had attained a good attraction in this field. Delayed wound healing is one of the most challenging clinical medicine complications. This study aimed to evaluate the collagen chitosan scaffold’s effect alone, or enriched with either bone marrow-derived mesenchymal stem cells (BM-MSCs) or their secreted extracellular vesicles (EVs) on the duration and quality of skin wound healing. Methods A full-thickness skin wound was induced on the back of 32 adult male Sprague-Dawley rats. The wounds were either covered with collagen chitosan scaffolds alone, scaffolds enriched with stem cells, or extracellular vesicles. Unprotected wounds were used as control. Healing duration, collagen deposition and alignment, CD 68+ macrophage count, and functional tensile strength of healed skin were assessed (α = 0.05, n = 8). Results The rate of skin healing was significantly accelerated in all treated groups compared to the control. Immuno-histochemical assessment of CD68+ macrophages showed enhanced macrophages count, in addition to higher collagen deposition and better collagen alignment in EVs and BM-MSCs treated groups compared to the control group. Higher tensile strength values reflected the better collagen deposition and alignment for these groups. EVs showed higher amounts of collagen deposition and better alignment compared to MSCs treated group. Conclusion The collagen chitosan scaffolds enriched with MSCs or their EVs improved wound healing and improved the quantity and remodeling of collagen with a better assignment to EVs.

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