Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion
Tóm tắt
Hepatic transdifferentiation of bone marrow cells has been previously demonstrated by intravenous administration of donor cells, which may recirculate to the liver after undergoing proliferation and differentiation in the recipient's bone marrow. In the present study, to elucidate which cellular components of human bone marrow more potently differentiate into hepatocytes, we fractionated human bone marrow cells into mesenchymal stem cells (MSCs), CD34+ cells, and non-MSCs/CD34- cells and examined them by directly xenografting to allylalcohol (AA)-treated rat liver. Hepatocyte-like cells, as revealed by positive immunostaining for human-specific alpha-fetoprotein (AFP), albumin (Alb), cytokeratin 19 (CK19), cytokeratin 18 (CK18), and asialoglycoprotein receptor (AGPR), and by reverse transcription-polymerase chain reaction (RT-PCR) for expression of AFP and Alb mRNA, were observed only in recipient livers with MSC fractions. Cell fusion was not likely involved since both human and rat chromosomes were independently identified by fluorescence in situ hybridization (FISH). The differentiation appeared to follow the process of hepatic ontogeny, reprogramming of gene expression in the genome of MSCs, as evidenced by expression of the AFP gene at an early stage and the albumin gene at a later stage. In conclusion, we have demonstrated that MSCs are the most potent component in hepatic differentiation, as revealed by directly xenografting into rat livers. (Blood. 2005;106:756-763)
Tài liệu tham khảo
Schwartz RE, Reyes M, Koodie L, et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest.2002;109: 1291-1302.
Reyes M, Lund T, Lenvik T, et al. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood.2001;98: 2615-2625.
Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature.2002;418: 41-49.
Lee KD, Kuo TK, Whang-Peng J, et al. In vitro hepatic differentiation of human mesenchymal stem cells. Hepatology.2004;40: 1275-1284.
Lee OK, Kuo TK, Chen WM, et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood.2004;103: 1669-1675.
Jang YY, Collector MI, Baylin SB, et al. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol.2004;6: 532-539.
Alison MR, Poulsom R, Jeffery R, et al. Hepatocytes from non-hepatic adult stem cells. Nature.2000;406: 257.
Theise ND, Nimmakayalu M, Gardner R, et al. Liver from bone marrow in humans. Hepatology.2000;32: 11-16.
Korbling M, Katz RL, Khanna A, et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med.2002;346: 738-746.
Mallet VO, Mitchell C, Mezey E, et al. Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo. Hepatology.2002;35: 799-804.
Newsome PN, Johannessen I, Boyle S, et al. Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion. Gastroenterology.2003;124: 1891-1900.
Harris RG, Herzog EL, Bruscia EM, et al. Lack of a fusion requirement for development of bone marrow-derived epithelia. Science.2004;305: 90-93.
Theise ND, Badve S, Saxena R, et al. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology.2000;31: 235-240.
Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med.2000;6: 1229-1234.
Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell.2001;105: 369-377.
Danet GH, Luongo JL, Butler G, et al. C1qRp defines a new human stem cell population with hematopoietic and hepatic potential. Proc Natl Acad Sci U S A.2002;99: 10441-10445.
Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature.2003;422: 897-901.
Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature.2003;422: 901-904.
Wang X, Ge S, McNamara G, et al. Albumin-expressing hepatocyte-like cells develop in the livers of immune-deficient mice that received transplants of highly purified human hematopoietic stem cells. Blood.2003;101: 4201-4208.
Camargo FD, Finegold M, Goodell MA. Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J Clin Invest.2004;113: 1266-1270.
Almeida-Porada G, Porada C, Chamberlain J, et al. Formation of human hepatocytes by human hematopoietic stem cells in sheep. Blood.2004;15: 2582-2590.
Willenbring H, Bailey AS, Foster M, et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med.2004;10: 744-748.
Jung SA, Chung YH, Park NH, et al. Experimental model of hepatic fibrosis following repeated periportal necrosis induced by allylalcohol. Scand J Gastroenterol.2000;35: 969-975.
Kobune M, Kawano Y, Ito Y, et al. Telomerized human multipotent mesenchymal cells can differentiate into hematopoietic and cobblestone area-supporting cells. Exp Hematol.2003;31: 715-722.
Kawano Y, Kobune M, Yamaguchi M, et al. Ex vivo expansion of human umbilical cord hematopoietic progenitor cells using a coculture system with human telomerase catalytic subunit (hTERT)-transfected human stromal cells. Blood.2003;101: 532-540.
Yavorkovsky L, Lai E, Ilic Z, et al. Participation of small intraportal stem cells in the restitutive response of the liver to periportal necrosis induced by allyl alcohol. Hepatology.1995;21: 1702-1712.
Kohgo Y, Kato J, Nakaya R, et al. Production and characterization of specific asialoglycoprotein receptor antibodies. Hybridoma.1993;12: 591-598.
Wang X, Montini E, Al-Dhalimy M, et al. Kinetics of liver repopulation after bone marrow transplantation. Am J Pathol.2002;161: 565-574.
Herzog EL, Chai L, Krause DS. Plasticity of marrow-derived stem cells. Blood.2003;102: 3483-3493.
Pittenger MF, Mackay AM, Beck SC, et al. Multi-lineage potential of adult human mesenchymal stem cells. Science.1999;284: 143-147.
Barry FP, Boynton RE, Haynesworth S, et al. The monoclonal antibody SH-2, raised against human mesenchymal stem cells, recognizes an epitope on endoglin (CD105). Biochem Biophys Res Commun.1999;265: 134-139.
Barry F, Boynton R, Murphy M, et al. The SH-3 and SH-4 antibodies recognize distinct epitopes on CD73 from human mesenchymal stem cells. Biochem Biophys Res Commun.2001;289: 519-524.
Colter DC, Class R, DiGirolamo CM, et al. Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc Natl Acad Sci U S A.2000;97: 3213-3218.
Yoshida S, Furuhashi M, Suganuma N. Expression of asialoglycoprotein receptor in human fetal liver. Endocr J.1999;46: 67-73.
Reyes M, Verfaillie CM. Characterization of multipotent adult progenitor cells, a subpopulation of mesenchymal stem cells. Ann N Y Acad Sci.2001;938: 231-233.
Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol.2000;28: 875-884.
Wexler SA, Donaldson C, Denning-Kendall P, et al. Adult bone marrow is a rich source of human mesenchymal `stem' cells but umbilical cord and mobilized adult blood are not. Br J Haematol.2003;121: 368-374.
Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature.2002;416: 542-545.
Ying QL, Nichols J, Evans EP, et al. Changing potency by spontaneous fusion. Nature.2002;416: 545-548.
Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature.2003;425: 968-973.
Ishikawa F, Drake CJ, Yang S, et al. Transplanted human cord blood cells give rise to hepatocytes in engrafted mice. Ann N Y Acad Sci.2003;996: 174-185.
Weiss MC, Green H. Human-mouse hybrid cell lines containing partial complements of human chromosomes and functioning human genes. Proc Natl Acad Sci U S A.1967;58: 1104-1111.
Haruna Y, Saito K, Spaulding S, et al. Identification of bipotential progenitor cells in human liver development. Hepatology.1996;23: 476-481.
LeSage G, Glaser S, Alpini G. Regulation of cholangiocyte proliferation. Liver.2001;21: 73-80.
Petersen BE, Bowen WC, Patrene KD, et al. Bone marrow as a potential source of hepatic oval cells. Science.1999;284: 1168-1170.
Kakinuma S, Tanaka Y, Chinzei R, et al. Human umbilical cord blood as a source of transplantable hepatic progenitor cells. Stem Cells.2003;21: 217-227.
Sell S. Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology.2001;33: 738-750.
Price RJ, Mistry H, Wield PT, et al. Comparison of the toxicity of allyl alcohol, coumarin and menadione in precision-cut rat, guinea-pig, cynomolgus monkey and human liver slices. Arch Toxicol.1996;71: 107-111.