Interleukin-6 from Adipose-Derived Stem Cells Promotes Tissue Repair by the Increase of Cell Proliferation and Hair Follicles in Ischemia/Reperfusion-Treated Skin Flaps

Abstract

The most common postoperative complication after reconstructive surgery is flap necrosis. Adipose-derived stem cells (ADSCs) and their secretomes are reported to mediate skin repair. This study was designed to investigate whether conditioned media from ADSCs (ADSC-CM) protects ischemia/reperfusion- (I/R-) induced injury in skin flaps by promoting cell proliferation and increasing the number of hair follicles. The mouse flap model of ischemia was ligating the long thoracic vessels for 3 h, followed by blood reperfusion. ADSC-CM was administered to the flaps, and their survival was observed on postoperative day 5. ADSC-CM treatment led to a significant increase in cell proliferation and the number of hair follicles. IL-6 levels in the lysate and CM from ADSCs were significantly higher than those from Hs68 fibroblasts. Furthermore, a strong decrease in cell proliferation and the number of hair follicles was observed after treatment with IL-6-neutralizing antibodies or si-IL-6-ADSC. In addition, ADSC transplantation increased flap repair, cell proliferation, and hair follicle number in I/R injury of IL-6-knockout mice. In conclusion, IL-6 secreted from ADSCs promotes the survival of I/R-induced flaps by increasing cell proliferation and the number of hair follicles. ADSCs represent a promising therapy for preventing skin flap necrosis following reconstructive and plastic surgery.

Mesenchymal Stromal Cell-Conditioned Medium for Skin Diseases: A Systematic Review

“…Preclinical studies are mainly focused on wound healing (Shin et al, 2015;Lee et al, 2020;Narita et al, 2020;Oh et al, 2020), showing high rates in wound closure. MSC-CM may also be an effective treatment for decreasing hypertrophic scars (Arjunan et al, 2020;Hu et al, 2020), improving flap reperfusion (Mirabella et al, 2012;Cooper et al, 2018;Pu et al, 2019), and treating psoriasis (Seetharaman et al, 2019) and AD . Nevertheless, there was significant variability between studies in the cell source, cell treatment, method of delivery, disease model used to assess efficacy, ways of assessment, and outcome evaluation.…”

“…Four studies evaluated the effects of MSC-CM for treating ischemic wounds or flaps (Mirabella et al, 2012;Cooper et al, 2018;Pu et al, 2019; Table 6). MSCs were isolated from human adipose tissue Cooper et al, 2018;Pu et al, 2019) or human amniotic fluid (Mirabella et al, 2012). CM was collected from MSCs between passages 3 and 8 at 70-90% confluence.…”

“…A porcine skin-derived gelatine membrane soaked in either MSC-CM or saline was also tested (n = 5/group) (Mirabella et al, 2012). Both studies observed that the MSC-CM treatment group enhanced skin flap recovery, attenuated the necrotic area, increased hair growth, and stimulated angiogenesis as compared with controls (Mirabella et al, 2012;Pu et al, 2019). MSC-CM were also applied topically on flap ischemic wounds in six mice.…”

Influence of Human Platelet Lysate on Extracellular Matrix Deposition and Cellular Characteristics in Adipose-Derived Stem Cell Sheets

“…Particularly, MSCs cultivated in 3D structure are sensitive to medium supplemented with HPL, resulting in changes in actin filament formation, mitochondrial dynamics and membrane elasticity that can have an impact on the immunomodulatory function of MSCs (Pasztorek et al, 2019). IL-6 is a regulator of inflammation, and previous reports have shown that IL-6 released from ASCs can increase proliferation of several types of cells (Lu et al, 2016;Pu et al, 2019). Since IL-6 was up-regulated in HPL-cultured ASC sheets, but not in the FBS counterparts, this finding may help to explain the stimulatory effects of conditioned medium of HPL-cultured ASC sheets on the migration and proliferation of fibroblasts in vitro.…”

Adipose-Derived Stem Cells Secretome and Its Potential Application in “Stem Cell-Free Therapy”

“…It has already been shown that co-treatment with administration of ASCs and conditioned ASCs media increases the proliferation of dermal keratinocytes and fibroblast in the skin [172] but also the maturation of fibroblasts associated with miR-24 upregulation [173]. Moreover, Pu et al showed that ASCs conditioned media prevent flap necrosis after skin flap transplantation by increasing proliferation and secretion of IL-6 [174]. Similarly, Bai et al showed that ASC-exos enhances skin flap recovery by reducing inflammation and apoptosis [175].…”