Application of Mesenchymal Stem Cells to Liver Regenerative Medicine

Abstract

本総説は，日本薬学会第 127 年会シンポジウム S45 で 発表したものを中心に記述したものである． Stem cell-based therapy has received attention as a possible alternative to organ transplantation, owing to the ability of stem cells to repopulate and diŠerentiate at the engrafted site. We transplanted bone marrow-derived mesenchymal stem cells (BMSCs) into liver-injured rats to test the therapeutic eŠect. Rat bone marrow cells were cultured in the presence of hepatocyte growth factor (HGF). RT-PCR and immunocytochemical analysis indicated that the BMSCs expressed the albumin mRNA and the production of protein after cultivation with HGF for 2 weeks. The BMSCs appeared to diŠerentiate into hepatocyte-like cells in response to the culture with HGF. After labeling with a ‰uorescent marker, the BMSCs were transplanted into CCl 4 -injured rats by injection through the caudal vein. The liver was excised and blood samples were collected 4 weeks later. Engraftment of the transplanted BMSCs was seen with signiˆcant ‰uores-cence in the injured liver. Transplantation of the BMSCs into liver-injured rats restored their serum albumin level and suppressed transaminase activity and liverˆbrosis. Therefore, BMSCs were shown to have a therapeutic eŠect on liver injury. Recently, we have been trying to use mesenchymal stem cells isolated from dental papilla of discarded human wisdom teeth. Autologous transplantation of mesenchymal stem cells from bone marrow and dental papilla could be ethically and functionally promising for stem cell-based therapy.

Prolonged survival by combined treatment with granulocyte colony‐stimulating factor and dipeptidyl peptidase IV inhibitor in a rat small‐for‐size liver transplantation model

“…Therefore, strategies to rescue SFS liver graft syndrome may have a dramatic impact on donor shortage. Liver regeneration can be performed via several mechanisms, including the transition of mature hepatocytes from the quiescent state into the cell cycle, the proliferative activity of hepatic progenitor cells, or the transdifferentiation of reservoir bone marrow‐derived stem cells (BMSC) or hematopoietic stem cells (HSC) into mature hepatocytes . Recent studies have shown that BMSC have the potential to inhibit the death of hepatocytes and promote liver regeneration after liver injury .…”

“…Liver regeneration can be performed via several mechanisms, including the transition of mature hepatocytes from the quiescent state into the cell cycle, the proliferative activity of hepatic progenitor cells, or the transdifferentiation of reservoir bone marrow-derived stem cells (BMSC) or hematopoietic stem cells (HSC) into mature hepatocytes. [1][2][3] Recent studies have shown that BMSC have the potential to inhibit the death of hepatocytes and promote liver regeneration after liver injury. [4][5][6][7][8] However, the therapeutic potential of BMSC for supporting liver regeneration and restore function of liver injury is not clear.…”

Implications of the immunoregulatory functions of mesenchymal stem cells in the treatment of human liver diseases

“…13 These secreted components of MSCs can enhance liver regeneration in a fulminant hepatic failure (FHF) model. 14 Several animal and clinical trials have demonstrated that MSCs have the potential to reverse the fibrotic process by inhibiting collagen deposition and transforming growth factor-b1 production and by their capacity to differentiate into hepatocytes. [15][16][17] The antifibrotic mechanism of MSC transplantation can be mainly attributed to the high levels of matrix metalloproteinase-9 expressed by MSCs, which may directly degrade the extracellular matrix 18 and indirectly regulate hepatic stellate cells to secrete cytokines.…”

Transplantation of ATP7B–Transduced Bone Marrow Mesenchymal Stem Cells Decreases Copper Overload in Rats

“…When co-cultured with hepatocytes, they promoted growth of the hepatocytes. When transplanted into liver, they likewise promoted the growth of hepatocytes in vivo , and accelerated restoration of function in damaged livers [19]. Studies have also shown that BM-MSCs migrate to a damaged liver and promote liver regeneration [20].…”