Extracellular Vesicles Containing MiR-146a-5p Secreted by Bone Marrow Mesenchymal Cells Activate Hepatocytic Progenitors in Regenerating Rat Livers

Overview

Journal Stem Cell Res Ther

Publisher Biomed Central

Date 2021 May 30

PMID 34051870

Citations 9

Authors

Norihisa Ichinohe

Masayuki Ishii

Naoki Tanimizu

Toru Mizuguchi

Yusuke Yoshioka

Takahiro Ochiya

Hiromu Suzuki

Toshihiro Mitaka

Affiliations

Soon will be listed here.

Abstract

Background: Small hepatocyte-like progenitor cells (SHPCs) appear to form transient clusters in rat livers treated with retrorsine (Ret) and 70% partial hepatectomy (PH). We previously reported that the expansion of SHPCs was amplified in Ret/PH-treated rat livers transplanted with Thy1 cells derived from D-galactosamine-treated injured livers. Extracellular vesicles (EVs) produced by hepatic Thy1 donor cells activated SHPCs via interleukin (IL)-17 receptor B signaling. As bone marrow-derived mesenchymal cells (BM-MCs) also express Thy1, we aimed to determine whether BM-MCs could also promote the growth of SHPCs.

Methods: BM-MCs were isolated from dipeptidyl-peptidase IV (DPPIV)-positive rats. BM-MCs or BM-MC-derived EVs were administered to DPPIV-negative Ret/PH rat livers, and the growth and the characteristics of SHPC clusters were evaluated 14 days post-treatment. miRNA microarrays and cytokine arrays examined soluble factors within EVs. Small hepatocytes (SHs) isolated from an adult rat liver were used to identify factors enhancing hepatocytic progenitor cells growth.

Results: The recipient's livers were enlarged at 2 weeks post-BM-MC transplantation. The number and the size of SHPCs increased remarkably in livers transplanted with BM-MCs. BM-MC-derived EVs also stimulated SHPC growth. Comprehensive analyses revealed that BM-MC-derived EVs contained miR-146a-5p, interleukin-6, and stem cell factor, which could enhance SHs' proliferation. Administration of EVs derived from the miR-146a-5p-transfected BM-MCs to Ret/PH rat livers remarkably enhanced the expansion of SHPCs.

Conclusions: miR-146a-5p involved in EVs produced by BM-MCs may play a major role in accelerating liver regeneration by activating the intrinsic hepatocytic progenitor cells.

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References

Ichinohe N, Nakano T, Mitaka T, Umakoshi Y, Tabata Y . Proliferation and osteogenic differentiation of rat bone marrow stromal cells on bioapatite with different crystalline facets. J Biomed Mater Res A. 2009; 93(2):646-55. DOI: 10.1002/jbm.a.32569. View

Petersen B, Goff J, Greenberger J, Michalopoulos G . Hepatic oval cells express the hematopoietic stem cell marker Thy-1 in the rat. Hepatology. 1998; 27(2):433-45. DOI: 10.1002/hep.510270218. View

Gilchrist E, Plevris J . Bone marrow-derived stem cells in liver repair: 10 years down the line. Liver Transpl. 2010; 16(2):118-29. DOI: 10.1002/lt.21965. View

Kon J, Ooe H, Oshima H, Kikkawa Y, Mitaka T . Expression of CD44 in rat hepatic progenitor cells. J Hepatol. 2006; 45(1):90-8. DOI: 10.1016/j.jhep.2006.01.029. View

Ichinohe N, Tanimizu N, Ooe H, Nakamura Y, Mizuguchi T, Kon J . Differentiation capacity of hepatic stem/progenitor cells isolated from D-galactosamine-treated rat livers. Hepatology. 2012; 57(3):1192-202. DOI: 10.1002/hep.26084. View

Chen Y, Chang M, Chien C, Wu S, Yu C, Chen H . Contribution of mature hepatocytes to small hepatocyte-like progenitor cells in retrorsine-exposed rats with chimeric livers. Hepatology. 2012; 57(3):1215-24. DOI: 10.1002/hep.26104. View

Zu Y, Yang Y, Zhu J, Bo X, Hou S, Zhang B . MiR-146a suppresses hepatocellular carcinoma by downregulating TRAF6. Am J Cancer Res. 2016; 6(11):2502-2513. PMC: 5126269. View

Zhou C, Jiang C, Zong Z, Lin J, Lao L . miR-146a promotes growth of osteosarcoma cells by targeting ZNRF3/GSK-3β/β-catenin signaling pathway. Oncotarget. 2017; 8(43):74276-74286. PMC: 5650339. DOI: 10.18632/oncotarget.19395. View

Tanimizu N, Kobayashi S, Ichinohe N, Mitaka T . Downregulation of miR122 by grainyhead-like 2 restricts the hepatocytic differentiation potential of adult liver progenitor cells. Development. 2014; 141(23):4448-56. DOI: 10.1242/dev.113654. View

10.

Bleau A, Redrado M, Nistal-Villan E, Villalba M, Exposito F, Redin E . miR-146a targets c-met and abolishes colorectal cancer liver metastasis. Cancer Lett. 2017; 414:257-267. DOI: 10.1016/j.canlet.2017.11.008. View

11.

Mitaka T, Mikami M, Sattler G, Pitot H, Mochizuki Y . Small cell colonies appear in the primary culture of adult rat hepatocytes in the presence of nicotinamide and epidermal growth factor. Hepatology. 1992; 16(2):440-7. DOI: 10.1002/hep.1840160224. View

12.

Keerthikumar S, Chisanga D, Ariyaratne D, Al Saffar H, Anand S, Zhao K . ExoCarta: A Web-Based Compendium of Exosomal Cargo. J Mol Biol. 2015; 428(4):688-692. PMC: 4783248. DOI: 10.1016/j.jmb.2015.09.019. View

13.

Taganov K, Boldin M, Chang K, Baltimore D . NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006; 103(33):12481-6. PMC: 1567904. DOI: 10.1073/pnas.0605298103. View

14.

Li K, Zhao B, Wei D, Wang W, Cui Y, Qian L . miR‑146a improves hepatic lipid and glucose metabolism by targeting MED1. Int J Mol Med. 2020; 45(2):543-555. PMC: 6984781. DOI: 10.3892/ijmm.2019.4443. View

15.

Lopatina T, Bruno S, Tetta C, Kalinina N, Porta M, Camussi G . Platelet-derived growth factor regulates the secretion of extracellular vesicles by adipose mesenchymal stem cells and enhances their angiogenic potential. Cell Commun Signal. 2014; 12:26. PMC: 4022079. DOI: 10.1186/1478-811X-12-26. View

16.

van Poll D, Parekkadan B, Cho C, Berthiaume F, Nahmias Y, Tilles A . Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology. 2008; 47(5):1634-43. DOI: 10.1002/hep.22236. View

17.

Huang B, Cheng X, Wang H, Huang W, la Ga Hu Z, Wang D . Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively. J Transl Med. 2016; 14:45. PMC: 4746907. DOI: 10.1186/s12967-016-0792-1. View

18.

Yin K, Wang S, Zhao R . Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomark Res. 2019; 7:8. PMC: 6450000. DOI: 10.1186/s40364-019-0159-x. View

19.

GORDON G, Coleman W, Grisham J . Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats. Am J Pathol. 2000; 157(3):771-86. PMC: 1885692. DOI: 10.1016/S0002-9440(10)64591-9. View

20.

Lu L, Boldin M, Chaudhry A, Lin L, Taganov K, Hanada T . Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell. 2010; 142(6):914-29. PMC: 3049116. DOI: 10.1016/j.cell.2010.08.012. View