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Hepatic stellate cells contribute to progenitor cells and liver regeneration
Claus Kordes, … , Diran Herebian, Dieter Häussinger
Claus Kordes, … , Diran Herebian, Dieter Häussinger
Published November 17, 2014
Citation Information: J Clin Invest. 2014;124(12):5503-5515. https://doi.org/10.1172/JCI74119.
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Research Article

Hepatic stellate cells contribute to progenitor cells and liver regeneration

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Abstract

Retinoid-storing hepatic stellate cells (HSCs) have recently been described as a liver-resident mesenchymal stem cell (MSC) population; however, it is not clear whether these cells contribute to liver regeneration or serve as a progenitor cell population with hepatobiliary characteristics. Here, we purified HSCs with retinoid-dependent fluorescence-activated cell sorting from eGFP-expressing rats and transplanted these GFP+ HSCs into wild-type (WT) rats that had undergone partial hepatectomy in the presence of 2-acetylaminofluorene (2AAF) or retrorsine, both of which are injury models that favor stem cell–based liver repair. Transplanted HSCs contributed to liver regeneration in host animals by forming mesenchymal tissue, progenitor cells, hepatocytes, and cholangiocytes and elevated direct bilirubin levels in blood sera of GUNN rats, indicating recovery from the hepatic bilirubin–handling defect in these animals. Transplanted HSCs engrafted within the bone marrow (BM) of host animals, and HSC-derived cells were isolated from BM and successfully retransplanted into new hosts with injured liver. Cultured HSCs transiently adopted an expression profile similar to that of progenitor cells during differentiation into bile acid–synthesizing and –transporting hepatocytes, suggesting that stellate cells represent a source of liver progenitor cells. This concept connects seemingly contradictory studies that favor either progenitor cells or MSCs as important players in stem cell–based liver regeneration.

Authors

Claus Kordes, Iris Sawitza, Silke Götze, Diran Herebian, Dieter Häussinger

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Figure 1

Characterization of freshly isolated HSCs from eGFP+ rats sorted by retinoid-dependent FACS.

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Characterization of freshly isolated HSCs from eGFP+ rats sorted by reti...
HSCs were enriched by density gradient centrifugation and further purified by FACS using (A) forward (FSC) and side scatter (SSC) as well as (B) retinoid fluorescence. HSCs with (A) similar morphological characteristics (gate R1) were (B) further analyzed for their retinoid fluorescence by UV light excitation. (B) HSCs with intense retinoid fluorescence (gate) were (C) cultured for 2 days and exhibited retinoid (blue) and eGFP (green) fluorescence as assessed by blue and UV light excitation of living cells. HSCs sorted by FACS expressed (D) GFAP, (E) nestin, and (F) vimentin (red), along with (D–F) desmin (green), as determined by immunofluorescence. Cell nuclei were stained with DAPI (blue). Scale bars: 100 μm (C); 50 μm (D–F).
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