Hepatic Stellate Cells Support Hematopoiesis and are Liver-Resident Mesenchymal Stem Cells

Abstract

Background/Aims: Hematopoiesis can occur in the liver, when the bone marrow fails to provide an adequate environment for hematopoietic stem cells. Hepatic stellate cells possess characteristics of stem/progenitor cells, but their contribution to hematopoiesis is not known thus far. Methods: Isolated hepatic stellate cells from rats were characterized with respect to molecular markers of bone marrow mesenchymal stem cells (MSC) and treated with adipocyte or osteocyte differentiation media. Stellate cells of rats were further co-cultured with murine stem cell antigen-1⁺ hematopoietic stem cells selected by magnetic cell sorting. The expression of murine hematopoietic stem cell markers was analyzed by mouse specific quantitative PCR during co-culture. Hepatic stellate cells from eGFP⁺ rats were transplanted into lethally irradiated wild type rats. Results: Desmin-expressing stellate cells were associated with hematopoietic sites in the fetal rat liver. Hepatic stellate cells expressed MSC markers and were able to differentiate into adipocytes and osteocytes in vitro. Stellate cells supported hematopoietic stem/progenitor cells during co-culture similar to bone marrow MSC, but failed to differentiate into blood cell lineages after transplantation. Conclusion: Hepatic stellate cells are liver-resident MSC and can fulfill typical functions of bone marrow MSC such as the differentiation into adipocytes or osteocytes and support of hematopoiesis.

Hepatic stellate cells contribute to progenitor cells and liver regeneration

“…In addition to these findings obtained with freshly isolated HSCs, single-cell clones of HSCs were established that preserved stellate cell characteristics and the ability to differentiate, indicating a self-renewal potential of HSCs. These important stem cell features further support the characterization of stellate cells as liver-resident MSCs (8,16). In line with their characterization as MSCs, engraftment of transplanted HSCs was also found in the BM of host animals, as demonstrated in the present study.…”

“…Recent data suggest that stellate cells represent liver-resident mesenchymal stem cells (MSCs) due to their MSC-related expression profile, their potential to differentiate into adipocytes or osteocytes, and their supportive effects on extramedullary hematopoiesis (8,9). In line with this, stellate cells can originate from the bone marrow (BM) (10,11), where MSCs were initially discovered (12), and reside in the liver close to endothelial cells, as is the case for MSCs in other organs (13).…”

Hepatic stem cell niches

“…Since MSCs are reported to occur in all organs (101), it is important to elucidate a possible function of MSCs in maintaining hepatic stem cell niches as supportive stromal cells. Interestingly, desmin-expressing hepatic stellate cells are closely associated with hematopoietic sites in the fetal liver and are suggested to support hematopoiesis as liver-resident MSCs (102,70,91,103). Similar to neuronal stem cells and bone marrow MSCs (33,104), hepatic stellate cells seem to fulfill a dual role as supportive cells on the one hand and precursor cells on the other.…”

The Role of Embryonic Stem Cell-expressed RAS (ERAS) in the Maintenance of Quiescent Hepatic Stellate Cells

“…Activated HSCs display an expression profile highly reminiscent of mesenchymal stem cells. Due to typical functions of mesenchymal stem cells, such as differentiation into adipocytes and osteocytes as well as support of hematopoietic stem cells, HSCs were identified as liver-resident mesenchymal stem cells (4).…”