The MSC-Derived Exosomal lncRNA H19 Promotes Wound Healing in Diabetic Foot Ulcers by Upregulating PTEN via MicroRNA-152-3p

Abstract

Mesenchymal stem cells (MSCs) have been reported to hold promise to accelerate the wound-healing process in diabetic foot ulcer (DFU) due to the multilineage differentiation potential. Hence, this study intended to explore the wound healing role of MSC-derived exosomes containing long noncoding RNA (lncRNA) H19 in DFU. lncRNA H19 was predicated to bind to microRNA-152-3p (miR-152-3p), which targeted phosphatase and tensin homolog (PTEN) deleted on chromosome ten. Fibroblasts in DFU samples exhibited highly expressed miR-152-3p and poorly expressed lncRNA H19 and PTEN, along with an activated phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt1) signaling pathway. The fibroblasts were cocultured with lncRNA H19-transfected MSCs and MSC-derived exosomes to assess the effect of the lncRNA H19/miR-152-3p/PTEN axis on the biological activities and inflammation in fibroblasts. Mouse models of DFU were developed by streptozotocin, which was injected with MSC-derived exosomes overexpressing lncRNA H19. lncRNA H19 in MSCs was transferred through exosomes to fibroblasts, the mechanism of which improved wound healing in DFU, corresponded to promoted fibroblast proliferation and migration, as well as suppressed apoptosis and inflammation. Wound healing in mice with DFU was facilitated following the injection of MSC-derived exosomes overexpressing lncRNA H19. Taken together, MSC-derived exosomal lncRNA H19 prevented the apoptosis and inflammation of fibroblasts by impairing miR-152-3p-mediated PTEN inhibition, leading to the stimulated wound-healing process in DFU.

Propagation and Maintenance of Cancer Stem Cells: A Major Influence of the Long Non-Coding RNA H19

“…Indeed, H19 can act not only as an intrinsic factor, but can also act on neighboring cells. For instance, the involvement of the exosomes-derived expression of H19 has been demonstrated in specific phenomena and pathologies such as trophoblast cell invasion, diabetic foot ulcers, and chronic cholestatic liver diseases, supporting our idea that exosomal H19 can extend its action to surrounding cells [96][97][98]. In cancer models, it has been demonstrated that H19 expression is upregulated in non-small cells lung cancer, particularly in gefitinib-resistant cells.…”

Mechanistic Actions of microRNAs in Diabetic Wound Healing

“…This indicates that something else other than MALAT1 is needed to enhance EV-mediated wound repair mechanisms. Yet, another exosomal-derived lncRNA H19 accelerated wound healing in mouse models of DFUs by suppressing miR-152-3p, thus resulting in an upregulation of PTEN [ 226 ].…”

Mesenchymal stem cell-derived exosomes: Toward cell-free therapeutic strategies in regenerative medicine

“…Therefore, menstrual blood derived MSC-Exos ameliorated cutaneous nonhealing DFUs. Moreover, Li et al[ 169 ] showed that bone marrow-derived MSC-Exos carrying lncRNA H19 promoted wound healing in mice with DFU by promoting fibroblast proliferation and migration and suppressing apoptosis and inflammation by inhibiting miR-152-3p and promoting PTEN expression.…”