Hypoxic Conditioned Medium From Human Adipose-Derived Stem Cells Promotes Mouse Liver Regeneration Through JAK/STAT3 Signaling

Abstract

Adipose-derived stem cells (ASCs) mainly exert their function by secreting materials that are collectively termed the secretome. Despite recent attention to the secretome as an alternative to stem cell therapy, the culture conditions for generating optimal secretome contents have not been determined. Therefore, we investigated the role of hypoxic-conditioned media (HCM) from ASCs. Normoxic-conditioned media (NCM) and HCM were obtained after culturing ASCs in 20% O 2 or 1% O 2 for 24 hours, respectively. Subsequently, partially hepatectomized mice were infused with saline, control medium, NCM, or HCM, and then sera and liver specimens were obtained for analyses. Hypoxia (1% O 2 ) significantly increased mRNA expression of mediators from ASCs, including interleukin-6 (IL-6), tumor necrosis factor a (TNF-a), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). HCM infusion significantly increased the number of Ki67-positive cells in the liver (p < .05). HCM infusion significantly increased phospho-signal transducer and activator of transcription 3 (STAT3) and decreased suppressor of cytokine signaling 3 (SOCS3) expression in the liver (p < .05). To determine the role of IL-6 in liver regeneration, we then performed IL-6 RNA interference study. Conditioned media (CM) obtained from ASCs, which were transfected with either siIL-6 or siControl, were administered to partially hepatectomized mice. The siIL-6 CM groups exhibited lower liver proliferation (Ki67-positive cells) and markers of regeneration (protein expression of proliferating cell nuclear antigen, p-STAT3, HGF, and VEGF and liver weights) than the siControl CM groups (p < .05). Taken together, hypoxic preconditioning of ASCs increased expression of mediators promoting anti-inflammatory and regenerative responses. The liver regenerative effects of HCM appear to be mediated by persistent and uninhibited expression of STAT3 in the liver, which results from decreased expression of SOCS3. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:816-825 SIGNIFICANCEIn this study, it was found that treatment with the medium from hypoxic-preconditioned adiposederived stem cells (ASCs) increased the viability of hepatotoxic hepatocytes and enhance liver regeneration in partially hepatectomized mice. In addition, the researchers first revealed that the hepatoprotective effects of hypoxic-conditioned media are mediated by persistent and uninhibited expression of signal transducer and activator of transcription 3 in the liver, which result from a decreased expression of suppressor of cytokine signaling 3. Therefore, the hypoxic preconditioning of ASCs is expected to play a crucial role in regenerative medicine by optimizing the production of a highly effective secretome from ASCs.

Brassica rapa Polysaccharides Ameliorate CCl4‐Induced Acute Liver Injury in Mice through Inhibiting Inflammatory Apoptotic Response and Oxidative Stress

“…JAK2 is a major member of the JAK protein family, which can be activated by many cytokines in vivo and phosphorylated with STAT3, an important member of the transcription activator family (STATs) that exists in the nucleus in the form of homologous dimer, to form a JAK2–STAT3 complex; this complex regulates the expression of inflammatory factors, such as TNF‐ α , IL‐1 β and IL‐6, in the liver. At the same time, various inflammatory factors can act on JAK2/STAT3 signaling pathway and further promote the inflammatory response . Therefore, inhibiting the JAK2‐STAT3 signaling pathway is essential to alleviate the inflammatory response and liver injury.…”

Conditioned Media From Adipose Tissue Derived Mesenchymal Stem Cells Reverse Insulin Resistance in Cellular Models

“…It has been reported that ADSCs‐CM treatment is as effective as ADSCs in treating pulmonary hypertension and pulmonary fibrosis and these beneficial effects of CM may provide an advanced approach to treat cardiopulmonary disorders [Rathinasabapathy et al, ]. It has also been established that hypoxic‐conditioned media of adipose‐derived stem cells increases the viability of hepatotoxic hepatocytes and augments liver regeneration in partially hepatectomized mice [Lee et al, ]. Although ADSCs‐CM has various application in wound healing, skin injury, brain injury, liver injury, and many more [Pawitan, ], the role of ADSCs‐CM in insulin resistance has not been established so far.…”

Large-scale quantitative genomics analyzes the circRNA expression profile and identifies the key circRNA in regulating cell proliferation during the proliferation phase of rat LR

“…Moreover, Stepniak et al reported that c-Jun/ AP-1 promoted G 1 /S transition in mice hepatocytes through a p53-dependent pathway after PH [28]. In addition, Wnt/ b-catenin, JAK-STAT and MAPK signalling pathways have been proved to be a major regulator of regeneration [29][30][31]. Overview, we hypothesized that DE circRNAs might regulate the expression of downstream mRNAs through their target miRNAs, thereby controlling cell proliferation through above signalling pathways in the proliferation phase of rats LR.…”