The role of bone marrow mesenchymal stromal cell derivatives in skin wound healing in diabetic mice

Abstract

Mesenchymal stromal cells (MSCs) have shown to be a promising tool in cell therapies to treat different conditions. Several pre-clinical and clinical studies have proved that the transplantation of MSCs improves wound healing. Here, we compare the beneficial effects of mouse bone marrow-derived allogeneic MSCs (allo-mBM-MSCs) and their acelullar derivatives (allo-acd-mMSCs) on skin wound healing in Non-Obese Diabetic (NOD) mice. One dose of allo-mBM-MSCs (1×106 cells) or one dose of allo-acd-mMSCs (1X) were intradermally injected around wounds in 8–10 week old female NOD mice. Wound healing was evaluated macroscopically (wound closure) every two days, and microscopically (reepithelialization, dermoepidermal junction, skin appendage regeneration, leukocyte infiltration, vascularization, granulation tissue formation, and density of collagen fibers in the dermis) after 16 days of MSC injection. In addition, we measured growth factors and specific proteins that were present in the allo-acd-mMSCs. Results showed significant differences in the wound healing kinetics of lesions that received allo-acd-mMSCs compared to lesions that received vehicle or allo-mBM-MSCs. In particular, mice treated with allo-acd-mMSCs reached significantly higher percentages of wound closure at day 4, 6 and 8, relative to the allo-mBM-MSCs and vehicle groups (p < 0.05), while wound closure percentages could not be statistically distinguished between the allo-mBM-MSCs and vehicle groups. Also, allo-acd-mMSCs had a greater influence in the skin would healing process. Specifically, they caused a less pronounced inflammatory severe response (p < 0.0001), more granulation tissue formation at an advanced stage (p < 0.0001), and higher density of collagen fibers (p < 0.05) compared to the other groups. Nevertheless, at day 16, both allo-mBM-MSCs and allo-acd-mMSCs revealed a higher effect on the recovery of the quality skin (continuous epidermis; regular dermoepidermal junction and skin appendages) relative to untreated lesions (p < 0.0001), but not between them. On the other hand, ELISA analyses indicated that the allo-acd-mMSCs contained growth factors and proteins relevant to wound healing such as IGF-1, KGF, HGF, VEGF, ANG-2, MMP-1, CoL-1 and PGE2. Compared to allo-acd-mMSCs, the administration of allo-mBM-MSCs is insufficient for wound healing in diabetic mice and delays the therapeutic effect, which maybe explained by the fact that trophic factors secreted by MSCs are critical for skin regeneration, and not the cells per se, suggesting that MSCs may require some time to secrete these factors after their administration.

A novel role of angiotensin II in epidermal cell lineage determination: Angiotensin II promotes the differentiation of mesenchymal stem cells into keratinocytes through the p38 MAPK, JNK and JAK2 signalling pathways

“…A total of 5 × 10 5 rat BM‐MSCs were seeded onto six‐well plates and cultured in respective condition medium. Alkaline phosphatase staining and Oil Red O staining were performed to confirm osteogenesis and adipogenesis, respectively …”

“…Optimum healing of a cutaneous wound requires a well‐orchestrated integration of complex biological and molecular events of cell migration and proliferation and includes extracellular matrix deposition and remodelling. Several studies in recent years have suggested that bone marrow‐derived stem cells such as mesenchymal stem cells (MSCs), progenitor cells such as endothelial progenitor cells and fibrocytes, may be involved in these processes, contributing to skin cells or releasing regulatory cytokines . Stem/progenitor cells may be mobilized to leave the bone marrow, migrate to injured tissues and participate in repair and regeneration .…”

Immunoinflammatory response and bioactive potential of GuttaFlow bioseal and MTA Fillapex in the rat subcutaneous tissue

“…Among the cytokines and growth factors, the interleukin-6 (IL-6) has a participation in the initiation and maintenance of the inflammatory reaction 4,5,[23][24][25] . Other chemokine involved in the inflammatory reaction is the vascular endothelial growth factor (VEGF), an angiogenic factor that increases the vascular permeability 26 favouring the recruitment of inflammatory cells in the beginning of the inflammatory reaction 27 , and plays an essential role in the tissue remodelling 28 and wound healing 27 .…”

Mesenchymal Stem Cell Therapies for Skin Repair and Regeneration

“…Bone marrow MSCs have been known to differentiate into a wide variety of mesenchymal cell types, including bone, cartilage and fat cells [9-11] and even into cells beyond its originating phenotype, such as cardiomyocytes and neurons [12,13]. In applications to the skin, bone marrow aspirate, bone marrow mononuclear cells, and a combination of cells and biomaterial have been used [14][15][16][17]. In a study utilizing autologous bone marrow aspirate [14], 75 patients with chronic wounds were enrolled.…”

“…Bone marrow MSCs have been explored as a treatment option [15][16][17]. In one study, allogeneic MSCs were compared to the MSCs' acellular derivatives in a non-obese diabetic (NOD) mouse model [15].…”