Human liver mesenchymal stem-progenitor cells inhibit hepatic stellate cell activation: in vitro and in vivo evaluationReportar como inadecuado

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Stem Cell Research and Therapy

, 8:131

First Online: 05 June 2017Received: 21 December 2016Revised: 03 May 2017Accepted: 05 May 2017DOI: 10.1186-s13287-017-0575-5

Cite this article as: Najimi, M., Berardis, S., El-Kehdy, H. et al. Stem Cell Res Ther 2017 8: 131. doi:10.1186-s13287-017-0575-5


BackgroundProgressive liver fibrosis leads to cirrhosis and end-stage liver disease. This disease is a consequence of strong interactions between matrix-producing hepatic stellate cells HSCs and resident and infiltrating immune cell populations. Accumulated experimental evidence supports the involvement of adult-derived human liver mesenchymal stem-progenitor cells ADHLSCs in liver regeneration. The aim of the present study was to evaluate the influence of ADHLSCs on HSCs, both in vitro and in vivo.

MethodsActivated human HSCs were co-cultured with ADHLSCs or ADHLSC-conditioned culture medium. The characteristics of the activated human HSCs were assessed by microscopy and biochemical assays, whereas proliferation was analyzed using flow cytometry and immunocytochemistry. The secretion profile of activated HSCs was evaluated by ELISA and Luminex. ADHLSCs were transplanted into a juvenile rat model of fibrosis established after co-administration of phenobarbital and CCl4.

ResultsWhen co-cultured with ADHLSCs or conditioned medium, the proliferation of HSCs was inhibited, beginning at 24 h and for up to 7 days. The HSCs were blocked in G0-G1 phase, and showed decreased Ki-67 positivity. Pro-collagen I production was reduced, while secretion of HGF, IL-6, MMP1, and MMP2 was enhanced. Neutralization of HGF partially blocked the inhibitory effect of ADHLSCs on the proliferation and secretion profile of HSCs. Repeated intrahepatic transplantation of cryopreserved-thawed ADHLSCs without immunosuppression inhibited the expression of markers of liver fibrosis in 6 out of 11 rats, as compared to their expression in the vehicle-transplanted group.

ConclusionsThese data provide evidence for a direct inhibitory effect of ADHLSCs on activated HSCs, which supports their development for the treatment of liver fibrosis.

KeywordsLiver Liver fibrosis Liver stem-progenitor cells Hepatic stellate cells Secretome AbbreviationsADHLSCsAdult-derived human liver mesenchymal stem-progenitor cells

DMEMDulbecco’s modified Eagle’s medium

HGFHepatocyte growth factor

HSCHepatic stellate cells

IL-6Interleukin 6

MMP1Metalloproteinase 1, MMP2, Metalloproteinase 2

MSCMesenchymal stem cells

Electronic supplementary materialThe online version of this article doi:10.1186-s13287-017-0575-5 contains supplementary material, which is available to authorized users.

Autor: Mustapha Najimi - Silvia Berardis - Hoda El-Kehdy - Valérie Rosseels - Jonathan Evraerts - Catherine Lombard - Adil El Tag


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