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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 2

Transplanted eGFP+ HSCs home to the injured WT host liver and contribute to liver regeneration (2AAF/PHX model).

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Transplanted eGFP+ HSCs home to the injured WT host liver and contribute...
eGFP immunofluorescence (green) of (A) WT control livers and WT host livers (B) 7 and (C) 14 days after HSC transplantation. qPCR of (D) Sry DNA and (E) eGFP mRNA on days 1, 7, and 14 after transplantation of male eGFP+ HSCs (n = 5). Livers of (D) males (n = 6) and females (n = 4) or (E) transgenic eGFP+ (100%, n = 3) and WT rats (0%, n = 3) were used for normalization. (F) qPCR of Col1a2 chain, Col4a1 chain, and Acta2 in rat livers from the 2AAF/PHX model with (n = 5) and without (control, n = 8) transplanted HSCs on day 14. (G and H) DAB immunohistochemistry of eGFP (brown) in WT host liver 1 day after HSC transplantation. (G) eGFP+ HSCs were identified by desmin immunofluorescence (yellow; zone 2). (H) HSC-derived cells within (black arrow) or associated with (white arrow) bile ducts (zone 1). (I) WT control liver without DAB immunohistochemistry of eGFP. (J–M) DAB staining of eGFP (brown) 14 days after transplantation of eGFP+ HSCs. (J) K19-expressing cells (yellow) in bile ducts with (J and K) eGFP are indicated with arrows (zone 1). eGFP+ hepatocytes (brown; arrows) identified by HNF4α immunofluorescence (yellow) (L) in zone 1 and (M) zone 3. (N) Fast red staining of eGFP+ (red) hepatocytes with HNF4a (yellow; arrows; zone 1). (O) eGFP fast red staining of WT control liver. Scale bars: 200 μm (A–C, I, and O); 50 μm (G and J–N); 20 μm (H).
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