Therapeutic Effects of Induced Pluripotent Stem Cells in Chimeric Mice with β-thalassemia

Overview

Journal Haematologica

Specialty Hematology

Date 2014 May 13

PMID 24816238

Citations 8

Authors

Guanheng Yang

Wansheng Shi

Xingyin Hu

Jingzhi Zhang

Zhijuan Gong

Xinbing Guo

Zhaorui Ren

Fanyi Zeng

Affiliations

Soon will be listed here.

Abstract

Although β-thalassemia is one of the most common human genetic diseases, there is still no effective treatment other than bone marrow transplantation. Induced pluripotent stem cells have been considered good candidates for the future repair or replacement of malfunctioning organs. As a basis for developing transgenic induced pluripotent stem cell therapies for thalassemia, β(654) induced pluripotent stem cells from a β(654) -thalassemia mouse transduced with the normal human β-globin gene, and the induced pluripotent stem cells with an erythroid-expressing reporter GFP were used to produce chimeric mice. Using these chimera models, we investigated changes in various pathological indices including hematologic parameters and tissue pathology. Our data showed that when the chimerism of β(654) induced pluripotent stem cells with the normal human β-globin gene in β(654) mice is over 30%, the pathology of anemia appeared to be reversed, while chimerism ranging from 8% to 16% provided little improvement in the typical β-thalassemia phenotype. Effective alleviation of thalassemia-related phenotypes was observed when chimerism with the induced pluripotent stem cells owning the erythroid-expressing reporter GFP in β(654) mouse was greater than 10%. Thus, 10% or more expression of the exogenous normal β-globin gene reduces the degree of anemia in our β-thalassemia mouse model, whereas treatment with β(654) induced pluripotent stem cells which had the normal human β-globin gene had stable therapeutic effects but in a more dose-dependent manner.

Citing Articles

Gene Editing of the Endogenous Cryptic 3' Splice Site Corrects the RNA Splicing Defect in the β-Thalassemia Mouse Model.

Lu D, Gong X, Guo X, Cai Q, Chen Y, Zhu Y Hum Gene Ther. 2024; 35(19-20):825-837.

PMID: 39078325 PMC: 11514127. DOI: 10.1089/hum.2023.202.

Correction of Beta-Thalassemia IVS-II-654 Mutation in a Mouse Model Using Prime Editing.

Zhang H, Sun R, Fei J, Chen H, Lu D Int J Mol Sci. 2022; 23(11).

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Correction of RNA splicing defect in β-thalassemia mice using CRISPR/Cas9 gene-editing technology.

Lu D, Gong X, Fang Y, Guo X, Chen Y, Yang F Haematologica. 2021; 107(6):1427-1437.

PMID: 34706494 PMC: 9152980. DOI: 10.3324/haematol.2020.278238.

Effect of Exogenous Transcription Factors Integration Sites on Safety and Pluripotency of Induced Pluripotent Stem Cells.

Yin S, Li W, Yang G, Cheng Y, Yi Q, Fan S Balkan J Med Genet. 2020; 23(1):5-13.

PMID: 32953404 PMC: 7474223. DOI: 10.2478/bjmg-2020-0003.

An overview of development in gene therapeutics in China.

Wang D, Wang K, Cai Y Gene Ther. 2020; 27(7-8):338-348.

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References

Huang S, Zeng F, Ren Z, Lu Z, Rodgers G, Schechter A . RNA transcripts of the beta-thalassaemia allele IVS-2-654 C-->T: a small amount of normally processed beta-globin mRNA is still produced from the mutant gene. Br J Haematol. 1994; 88(3):541-6. DOI: 10.1111/j.1365-2141.1994.tb05071.x. View

Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini M, Del Vecchio G . Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004; 89(10):1187-93. View

Musto P, Lombardi G, Centra M, Modoni S, Carotenuto M, Di Giorgio G . Soluble transferrin receptor in beta-thalassaemia. Lancet. 1993; 342(8878):1058. DOI: 10.1016/0140-6736(93)92916-h. View

Corradini E, Garuti C, Montosi G, Ventura P, Andriopoulos Jr B, Lin H . Bone morphogenetic protein signaling is impaired in an HFE knockout mouse model of hemochromatosis. Gastroenterology. 2009; 137(4):1489-97. PMC: 2757523. DOI: 10.1053/j.gastro.2009.06.057. View

Kazazian Jr H, Boehm C . Molecular basis and prenatal diagnosis of beta-thalassemia. Blood. 1988; 72(4):1107-16. View

Kautz L, Meynard D, Besson-Fournier C, Darnaud V, Al Saati T, Coppin H . BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression. Blood. 2009; 114(12):2515-20. DOI: 10.1182/blood-2009-02-206771. View

Andreani M, Testi M, Gaziev J, Condello R, Bontadini A, Tazzari P . Quantitatively different red cell/nucleated cell chimerism in patients with long-term, persistent hematopoietic mixed chimerism after bone marrow transplantation for thalassemia major or sickle cell disease. Haematologica. 2010; 96(1):128-33. PMC: 3012776. DOI: 10.3324/haematol.2010.031013. View

Bartnikas T, Andrews N, Fleming M . Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice. Blood. 2010; 117(2):630-7. PMC: 3031485. DOI: 10.1182/blood-2010-05-287359. View

Ruggeri A, Eapen M, Scaravadou A, Cairo M, Bhatia M, Kurtzberg J . Umbilical cord blood transplantation for children with thalassemia and sickle cell disease. Biol Blood Marrow Transplant. 2011; 17(9):1375-82. PMC: 3395002. DOI: 10.1016/j.bbmt.2011.01.012. View

10.

Rivella S, May C, Chadburn A, Riviere I, Sadelain M . A novel murine model of Cooley anemia and its rescue by lentiviral-mediated human beta-globin gene transfer. Blood. 2002; 101(8):2932-9. DOI: 10.1182/blood-2002-10-3305. View

11.

Gringras P, Wonke B, Old J, Fitches A, Valler D, Kuan A . Effect of alpha thalassaemia trait and enhanced gamma chain production on disease severity in beta thalassaemia major and intermedia. Arch Dis Child. 1994; 70(1):30-4. PMC: 1029678. DOI: 10.1136/adc.70.1.30. View

12.

Cook J, Skikne B, Baynes R . Serum transferrin receptor. Annu Rev Med. 1993; 44:63-74. DOI: 10.1146/annurev.me.44.020193.000431. View

13.

Lewis J, Yang B, Kim R, Sierakowska H, Kole R, SMITHIES O . A common human beta globin splicing mutation modeled in mice. Blood. 1998; 91(6):2152-6. View

14.

Lisini D, Zecca M, Giorgiani G, Montagna D, Cristantielli R, Labirio M . Donor/recipient mixed chimerism does not predict graft failure in children with beta-thalassemia given an allogeneic cord blood transplant from an HLA-identical sibling. Haematologica. 2008; 93(12):1859-67. DOI: 10.3324/haematol.13248. View

15.

Imren S, Payen E, Westerman K, Pawliuk R, Fabry M, Eaves C . Permanent and panerythroid correction of murine beta thalassemia by multiple lentiviral integration in hematopoietic stem cells. Proc Natl Acad Sci U S A. 2002; 99(22):14380-5. PMC: 137892. DOI: 10.1073/pnas.212507099. View

16.

Krishnamurti L, Kharbanda S, Biernacki M, Zhang W, Baker K, Wagner J . Stable long-term donor engraftment following reduced-intensity hematopoietic cell transplantation for sickle cell disease. Biol Blood Marrow Transplant. 2008; 14(11):1270-8. DOI: 10.1016/j.bbmt.2008.08.016. View

17.

Cazzola M, Beguin Y, Bergamaschi G, Guarnone R, Cerani P, Barella S . Soluble transferrin receptor as a potential determinant of iron loading in congenital anaemias due to ineffective erythropoiesis. Br J Haematol. 1999; 106(3):752-5. DOI: 10.1046/j.1365-2141.1999.01600.x. View

18.

Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang R . Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008; 112(4):1503-9. DOI: 10.1182/blood-2008-03-143354. View

19.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

20.

Tamagnini G, Lopes M, Castanheira M, Wainscoat J, Wood W . Beta + thalassemia--Portuguese type: clinical, haematological and molecular studies of a newly defined form of beta thalassaemia. Br J Haematol. 1983; 54(2):189-200. DOI: 10.1111/j.1365-2141.1983.tb02087.x. View