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Stem Cell Research and Therapy

, 8:181

First Online: 03 August 2017Received: 07 March 2017Revised: 11 July 2017Accepted: 20 July 2017

Abstract

BackgroundA hypoxic-preconditioned secretome from stem cells reportedly promotes the functional and regenerative capacity of the liver more effectively than a control secretome. However, the optimum oxygen partial pressure pO2 in the cell culture system that maximizes the therapeutic potential of the secretome has not yet been determined.

MethodsWe first determined the cellular alterations in adipose tissue-derived stem cells ASCs cultured under different pO2 21%, 10%, 5%, and 1%. Subsequently, partially hepatectomized mice were injected with the secretome of ASCs cultured under different pO2, and then sera and liver specimens were obtained for analyses.

ResultsOf all AML12 cells cultured under different pO2, the AML12 cells cultured under 1% pO2 showed the highest mRNA expression of proliferation-associated markers IL-6, HGF, and VEGF. In the cell proliferation assay, the AML12 cells cultured with the secretome of 1% pO2 showed the highest cell proliferation, followed by the cells cultured with the secretome of 21%, 10%, and 5% pO2, in that order. When injected into the partially hepatectomized mice, the 1% pO2 secretome most significantly increased the number of Ki67-positive cells, reduced serum levels of proinflammatory mediators IL-6 and TNF-α, and reduced serum levels of liver transaminases. In addition, analysis of the liver specimens indicated that injection with the 1% pO2 secretome maximized the expression of the intermediate molecules of the PIP3-Akt and IL-6-STAT3 signaling pathways, all of which are known to promote liver regeneration.

ConclusionsThe data of this study suggest that the secretome of ASCs cultured under 1% pO2 has the highest liver reparative and regenerative potential of all the secretomes tested here.

KeywordsAdipose tissue-derived stem cells Hypoxia Liver regeneration Sirtuin-1 SIRT1 Secretome AbbreviationsAKTSerine-Threonine-protein kinase

ALTAlanine transaminase

ASTAspartate transaminase

ASCAdipose tissue-derived stem cell

ATCCAmerican Type Culture Collection

CMConditioned medium

Baxbcl-2-like protein 4

Bcl-xLB-cell lymphoma—extra large

c-Cas3Cleaved caspase-3

ERKExtracellular signal-regulated kinase

FBSFetal bovine serum

HGFHepatocyte growth factor

HIF-1αHypoxia-inducible factor-1α

HPHypoxic preconditioning

Mcl-1Myeloid cell leukemia-1

MSCMesenchymal stem cell

PIP3Phosphatidylinositol-3,4,5-triphosphate

p38MAPKp38 mitogen-activated protein kinase

PBSPhosphate-buffered saline

PCNAProliferating cell nuclear antigen

p-STAT3Phospho-signal transducer and activator of transcription 3

RT-qPCRReverse-transcription qPCR

SDStandard deviation

SIRT1NAD-dependent deacetylase sirtuin-1

VEGFVascular endothelial growth factor

Electronic supplementary materialThe online version of this article doi:10.1186-s13287-017-0635-x contains supplementary material, which is available to authorized users.

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Autor: Sang Chul Lee - Kee-Hwan Kim - Ok-Hee Kim - Sang Kuon Lee - Ha-Eun Hong - Seong Su Won - Sang-Jin Jeon - Byung Jo Choi

Fuente: https://link.springer.com/



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