Human Keratinocyte-Derived Exosomal MALAT1 Promotes Diabetic Wound Healing by Upregulating MFGE8 via microRNA-1914-3p

Abstract

Purpose Diabetic wound is a highly prevalent and refractory disease. Extensive studies have confirmed that keratinocytes and macrophages play an important role in the process of wound healing. Additionally, exosomes are regarded as a vital intercellular communication tool. This study aimed to investigate the role of human keratinocyte-derived exosomal MALAT1 in the treatment of diabetic wound by influencing the biological function of macrophages. Methods We mainly assessed the function of MALAT1 on the biological changes of macrophages, and the expression of MALAT1 in the keratinocyte-exosomes analyzed by quantitative real-time polymerase chain reaction (RT-qPCR). The downstream interaction between RNAs or proteins was assessed by mechanistic experiments. Besides, we evaluated the effects of human keratinocyte-derived exosomal MALAT1 on diabetic wound healing in vivo to verify in vitro results. Results We demonstrated that human keratinocyte-derived exosomal MALAT1 enhanced the biological functions of high glucose-injured macrophages, including phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. Mechanistically, MALAT1 accelerated the expression of MFGE8 by competitively binding to miR-1914-3p, thereby affecting the function of macrophages and the signal axis of TGFB1/SMAD3, and finally promoting the healing of diabetic wounds. Human keratinocyte-derived exosomal MALAT1 might promote collagen deposition, ECM remodeling, and expression of MFGE8, VEGF, and CD31 but reduce the expression of TGFB and SMAD3 in an in vivo model of diabetic mice wounds, which accelerated diabetic wound healing and restored its function. Conclusion The current study revealed that human keratinocyte-derived exosomal MALAT1 would suppress miR-1914-3p to activate MFGE8 and eventually promote wound healing by enhancing macrophage phagocytosis, converting to a pro-healing phenotype and reducing apoptosis. It proposed that keratinocyte-derived exosomes might have the capacity to serve as a new method for the clinical treatment of diabetic wound.

LncRNA MALAT1 in Keratinocyte function: A review of recent advances

“…The changes in miR-1914-3p and MFGE8 expression influenced macrophage phagocytosis, apoptosis, and polarization through the TGFB1/SMAD3 signaling pathway. Finally, the authors confirmed that exosomes derived from KCs carrying MALAT1 could regulate the expression of miR-1914-3p and MFGE8 in macrophages [ 39 ]. In another study, Li-Wen Kuang and collaborators aimed to investigate the possible positive feedback loops involving lncRNAs in diabetic wound healing through mice and an in vitro keratinocyte model.…”

Epigenetic modification: A novel insight into diabetic wound healing

“…By encouraging the production of STAT1, the lncRNA GAS5 converts M1 macrophages into M2 macrophages, which in turn enhances diabetic wound healing [ 162 ]. Human keratinocyte-derived exosomal MALAT1 upregulated MFGE8 through miRNA-1914-3p, thereby enhancing macrophage phagocytosis, converting to M2 phenotype and reducing apoptosis to promote diabetic wound healing [ 163 ].…”

“…Extracellular vesicles (EVs) have a high degree of safety and stability and can enhance the effectiveness of diabetic wound healing by artificially modulating the ncRNAs they carry [ 205 ]. For instance, MFGE8 is upregulated by the human keratinocyte-derived exosome MALAT1 via miRNA-1914-3p, which facilitates macrophage polarization to M2 phenotype and diabetic wound healing [ 163 ]. Similarly, circ-Snhg11 in exosomes derived from hypoxic ADSCs affects HIF-1α expression via miR-144-3p, promotes wound M2 macrophage polarization and attenuates inflammatory responses in diabetic mice [ 170 ].…”

“… Application in diabetic wound healing Related ncRNA Effect Refs NcRNA delivered by extracellular vesicle delivery platform MALAT1, miRNA-1914-3p MALAT1 in human keratinocyte-derived exosomes upregulates MFGE8 via miRNA-1914-3p, thereby promoting macrophage polarization to M2 phenotype and diabetic wound healing. [ 163 ] circ-Snhg11 circ-Snhg11 in hypoxic ADSCS-derived exosomes induces polarization of M2 macrophages by targeting miR-144-3p and HIF-1α, alleviating diabetic wound inflammation. [ 170 ] mmu_circ_0001052 mmu_circ_0001052 in exosomes produced from ADSCs promotes DFU angiogenesis by sponging miR-106a-5p via the FGF4/p38MAPK pathway.…”

Deciphering The Emerging Role of Programmed Cell Death in Diabetic Wound Healing

“…On the one hand, this hindered the transformation of M1 to M2 macrophages, and on the other hand, it could also lead to a failure to remove apoptotic cells from the wound in a timely manner, and the increased apoptotic cells might delay the repair process 73 . Exosomal MALAT1 derived from human KCs could enhance HG-injured macrophage functions and reduce apoptosis by suppressing miR-1914-3p to activate milk fat globule-EGF factor 8 (MFGE8), leading to a facilitation of wound healing 74 . Taken together, it is evident that both neutrophils and macrophages are disturbed in diabetic wounds.…”