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Exp Clin Endocrinol Diabetes 2021; 129(05): 357-364
DOI: 10.1055/a-1103-1900
Article

Class I and II Histone Deacetylase Inhibitor LBH589 Promotes Endocrine Differentiation in Bone Marrow Derived Human Mesenchymal Stem Cells and Suppresses Uncontrolled Proliferation

Christoph Schröder‡
1   Clinical Research Unit, Centre of Internal Medicine, Justus Liebig University Giessen, Germany
2   Medizinische Hochschule Hannover, Hannover, Germany
,
Rahul Khatri‡
1   Clinical Research Unit, Centre of Internal Medicine, Justus Liebig University Giessen, Germany
,
Sebastian Friedrich Petry
1   Clinical Research Unit, Centre of Internal Medicine, Justus Liebig University Giessen, Germany
,
Thomas Linn
1   Clinical Research Unit, Centre of Internal Medicine, Justus Liebig University Giessen, Germany
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Abstract

Mesenchymal stem cells are useful tools employed in clinical and preclinical medicine. Their beneficial potential in especially degenerative as well as autoimmune diseases is a constant focus of research. Regarding diabetes mellitus, transplantation of stem cells is seen as a possible therapeutic approach to overcome the loss of endocrine pancreatic cells. It was reported that co-transplantation of mesenchymal stem cells with pancreatic islet cells improves function and survival of the graft. However, these multipotent progenitors may be able to form tumors, especially under immunosuppressed conditions. Histone deacetylase inhibitors might offer the potential to overcome this issue. These small molecules can induce cell differentiation and control proliferation. Their potential to control lineage development of stem cells has been distinctly demonstrated in the treatment of cancer, mainly in hematopoietic neoplasias.

In this study, we demonstrate that human bone marrow-derived mesenchymal stem cells exhibit low carcinogenic potential in an immunosuppressed condition in vivo. Further, the effect of histone deacetylase inhibitors LBH589, MS-275, and MGCD0103 was examined after normalizing histone deacetylase activities in culture. Interestingly, transcripts of insulin gene enhancer protein and paired-box-gene 6, two markers of pancreatic endocrine differentiation were constitutively expressed in the cell line. The broad spectrum inhibitor of class I and class II histone deacetylases LBH589 upregulated the expression of these transcription factors in a significant way, whereas addition of selective class I histone deacetylase inhibitors MS-275 and MGCD0103 did not result in significant changes in gene expression.

In conclusion, we deliver evidence that a combined class I and II histone deacetylase inhibition is able to modulate the transcripts of differentiation markers of mesenchymal stem cells. The treatment holds the capability to facilitate endocrine differentiation in future approaches to replace endocrine cells by stem cell therapy.

Key words

HDAC - Isl1 - Pax6 - islet transplantation - tumor formation

Supplementary Material



Publication History

Received: 22 July 2019
Received: 27 December 2019

Accepted: 20 January 2020

Article published online:
12 February 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Dominici M, Le Blanc K, Mueller I. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315-317
    CrossrefPubMedGoogle Scholar
  • 2 Jiang Y, Jahagirdar BN, Reinhardt RL. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41-49
    CrossrefPubMedGoogle Scholar
  • 3 Abdallah BM, Haack-Sorensen M, Burns JS. et al. Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite corrected extensive proliferation. Biochem Biophys Res Commun 2005; 326: 527-538
    CrossrefPubMedGoogle Scholar
  • 4 Pittenger MF, Mackay AM, Beck SC. et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143-147
    CrossrefPubMedGoogle Scholar
  • 5 Chang K-A, Lee J-H, Suh Y-H. Therapeutic potential of human adipose-derived stem cells in neurological disorders. J Pharmacol Sci 2014; 126: 293-301
    CrossrefPubMedGoogle Scholar
  • 6 Timper K, Seboek D, Eberhardt M. et al. Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun 2006; 341: 1135-1140
    CrossrefPubMedGoogle Scholar
  • 7 Arzouni AA, Vargas-Seymour A, Nardi N. et al. Using mesenchymal stromal cells in islet transplantation. Stem Cells Transl Med 2018; 7: 559-563
    CrossrefPubMedGoogle Scholar
  • 8 He Y, Zhang D, Zeng Y. et al. Bone marrow-derived mesenchymal stem cells protect islet grafts against endoplasmic reticulum stress-induced apoptosis during the early stage after transplantation. Stem Cells 2018; 36: 1045-1061
    CrossrefPubMedGoogle Scholar
  • 9 Tanaka T, Kojima D, Mera T. et al. Expansion of transplanted islets in mice by co-transplantation with adipose tissue-derived mesenchymal stem cells. Heliyon 2018; DOI: 10.1016/j.heliyon.2018.e00632..
    CrossrefPubMedGoogle Scholar
  • 10 Watanabe H, Tsuchiya T, Shimoyama K. et al. Adipose-derived mesenchymal stem cells attenuate rejection in a rat lung transplantation model. J Surg Res 2018; 227: 17-27
    CrossrefPubMedGoogle Scholar
  • 11 Finnin MS, Donigian JR, Cohen A. et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999; 401: 188-193
    CrossrefPubMedGoogle Scholar
  • 12 Peart MJ, Smyth GK, van Laar RK. et al. Identification and functional significance of genes regulated by structurally different histone deacetylase inhibitors. Proc Natl Acad Sci USA 2005; 102: 3697-3702
    CrossrefPubMedGoogle Scholar
  • 13 de Ruijter Annemieke JM, van Gennip AH, Caron HN. et al. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem J 2003; 370: 737-749
    CrossrefPubMedGoogle Scholar
  • 14 Gao L, Cueto MA, Asselbergs F. et al. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J Biol Chem 2002; 277: 25748-25755
    CrossrefPubMedGoogle Scholar
  • 15 Boffa LC, Vidali G, Mann RS. et al. Suppression of histone deacetylation in vivo and in vitro by sodium butyrate. J Biol Chem 1978; 253: 3364-3366
    CrossrefPubMedGoogle Scholar
  • 16 Hu E, Dul E, Sung C-M. et al. Identification of novel isoform-selective inhibitors within class I histone deacetylases. J Pharmacol Exp Ther 2003; 307: 720-728
    CrossrefPubMedGoogle Scholar
  • 17 Fournel M, Bonfils C, Hou Y. et al. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther 2008; 7: 759-768
    CrossrefPubMedGoogle Scholar
  • 18 Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challenges. Cancer Lett 2009; 280: 233-241
    CrossrefPubMedGoogle Scholar
  • 19 Guha M. HDAC inhibitors still need a home run, despite recent approval. Nat Rev Drug Discov 2015; 14: 225-226
    CrossrefPubMedGoogle Scholar
  • 20 Mann BS, Johnson JR, Cohen MH. et al. FDA approval summary: Vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 2007; 12: 1247-1252
    CrossrefPubMedGoogle Scholar
  • 21 Andrew JY, Noopur SR. Panobinostat and multiple myeloma in 2018. Oncologist 2018; 23: 516-517
    CrossrefPubMedGoogle Scholar
  • 22 Bots M, Verbrugge I, Martin BP. et al. Differentiation therapy for the treatment of t(8;21) acute myeloid leukemia using histone deacetylase inhibitors. Blood 2014; 123: 1341-1352
    CrossrefPubMedGoogle Scholar
  • 23 Salmon JM, Bots M, Vidacs E. et al. Combining the differentiating effect of panobinostat with the apoptotic effect of arsenic trioxide leads to significant survival benefit in a model of t(8;21) acute myeloid leukemia. Clin Epigenetics 2015; 7: 2
    CrossrefPubMedGoogle Scholar
  • 24 Richon VM, Sandhoff TW, Rifkind RA. et al. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci USA 2000; 97: 10014-10019
    CrossrefPubMedGoogle Scholar
  • 25 Rekittke NE, Ang M, Rawat D. et al. Regenerative therapy of type 1 diabetes mellitus: From pancreatic islet transplantation to mesenchymal stem cells. Stem Cells Int 2016; 2016: 3764681
    CrossrefPubMedGoogle Scholar
  • 26 Karantzali E, Schulz H, Hummel O. et al. Histone deacetylase inhibition accelerates the early events of stem cell differentiation: transcriptomic and epigenetic analysis. Genome Biol 2008; 9: R65
    CrossrefPubMedGoogle Scholar
  • 27 Haumaitre C, Lenoir O, Scharfmann R. Directing cell differentiation with small-molecule histone deacetylase inhibitors: the example of promoting pancreatic endocrine cells. Cell Cycle 2009; 8: 536-544
    CrossrefPubMedGoogle Scholar
  • 28 Kurihara Y, Suzuki T, Sakaue M. et al. Valproic acid, a histone deacetylase inhibitor, decreases proliferation of and induces specific neurogenic differentiation of canine adipose tissue-derived stem cells. J Vet Med Sci 2014; 76: 15-23
    CrossrefPubMedGoogle Scholar
  • 29 Cvekl A, Callaerts P. PAX6: 25th anniversary and more to learn. Exp Eye Res 2017; 156: 10-21
    CrossrefPubMedGoogle Scholar
  • 30 Smith MA, Court EL, Smith JG. Stem cell factor: laboratory and clinical aspects. Blood Rev 2001; 15: 191-197
    CrossrefPubMedGoogle Scholar
  • 31 Ahlgren U, Pfaff SL, Jessell TM. et al. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature 1997; 385: 257-260
    CrossrefPubMedGoogle Scholar
  • 32 Luo H, Liu W-H, Liang H-Y. et al. Differentiation-inducing therapeutic effect of Notch inhibition in reversing malignant transformation of liver normal stem cells via MET. Oncotarget 2018; 9: 18885-18895
    CrossrefPubMedGoogle Scholar
  • 33 You N, Zheng L, Liu W. et al. Proliferation inhibition and differentiation induction of hepatic cancer stem cells by knockdown of BC047440: A potential therapeutic target of stem cell treatment for hepatocellular carcinoma. Oncol Rep 2014; 31: 1911-1920
    CrossrefPubMedGoogle Scholar
  • 34 Zhang Z, Zhou Y, Qian H. et al. Stemness and inducing differentiation of small cell lung cancer NCI-H446 cells. Cell Death Dis 2013; 4: e633
    CrossrefPubMedGoogle Scholar
  • 35 Tarte K, Gaillard J, Lataillade J-J. et al. Clinical-grade production of human mesenchymal stromal cells: Occurrence of aneuploidy without transformation. Blood 2010; 115: 1549-1553
    CrossrefPubMedGoogle Scholar
  • 36 Mishra PJ, Mishra PJ, Glod JW. et al. Mesenchymal stem cells: Flip side of the coin. Cancer Res 2009; 69: 1255-1258
    CrossrefPubMedGoogle Scholar
  • 37 Rubio D, Garcia S, La Cueva de T. et al. Human mesenchymal stem cell transformation is associated with a mesenchymal-epithelial transition. Exp Cell Res 2008; 314: 691-698
    CrossrefPubMedGoogle Scholar
  • 38 Abbasi-Malati Z, Roushandeh AM, Kuwahara Y. et al. Mesenchymal stem cells on horizon: A new arsenal of therapeutic agents. Stem Cell Rev 2018; 14: 484-499
    CrossrefPubMedGoogle Scholar
  • 39 Tang D-Q, Wang Q, Burkhardt BR. et al. In vitro generation of functional insulin-producing cells from human bone marrow-derived stem cells, but long-term culture running risk of malignant transformation. Am J Stem Cells 2012; 1: 114-127
    PubMedGoogle Scholar
  • 40 West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 2014; 124: 30-39
    CrossrefPubMedGoogle Scholar
  • 41 Rasheed WK, Johnstone RW, Prince HM. Histone deacetylase inhibitors in cancer therapy. Expert Opin Investig Drugs 2007; 16: 659-678
    CrossrefPubMedGoogle Scholar
  • 42 Thatava T, Tayaramma T, Ma B. et al. Chromatin-remodeling factors allow differentiation of bone marrow cells into insulin-producing cells. Stem Cells 2006; 24: 2858-2867
    CrossrefPubMedGoogle Scholar
  • 43 Yoo EJ, Chung J-J, Choe SS. et al. Down-regulation of histone deacetylases stimulates adipocyte differentiation. J Biol Chem 2006; 281: 6608-6615
    CrossrefPubMedGoogle Scholar
  • 44 Haumaitre C, Lenoir O, Scharfmann R. Histone deacetylase inhibitors modify pancreatic cell fate determination and amplify endocrine progenitors. Mol Cell Biol 2008; 28: 6373-6383
    CrossrefPubMedGoogle Scholar
  • 45 Wang Z, Qin G, Zhao TC. HDAC4: mechanism of regulation and biological functions. Epigenomics 2014; 6: 139-150
    CrossrefPubMedGoogle Scholar
  • 46 Yang X-J, Grégoire S. Class II histone deacetylases: From sequence to function, regulation, and clinical implication. Mol Cell Biol 2005; 25: 2873-2884
    CrossrefPubMedGoogle Scholar
  • 47 Fischle W, Kiermer V, Dequiedt F. et al. The emerging role of class II histone deacetylases. Biochem Cell Biol 2001; 79: 337-348
    CrossrefPubMedGoogle Scholar
  • 48 Mai A, Massa S, Pezzi R. et al. Class II (IIa)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxyamides. J Med Chem 2005; 48: 3344-3353
    CrossrefPubMedGoogle Scholar
  • 49 Martin M, Kettmann R, Dequiedt F. Class IIa histone deacetylases: Regulating the regulators. Oncogene 2007; 26: 5450-5467
    CrossrefPubMedGoogle Scholar
  • 50 Lenoir O, Flosseau K, Ma FX. et al. Specific control of pancreatic endocrine β- and δ-cell mass by class IIa histone deacetylases HDAC4, HDAC5, and HDAC9. Diabetes 2011; 60: 2861-2871
    CrossrefPubMedGoogle Scholar
  • 51 Simões-Pires CA, Bertrand P, Cuendet M. Novel histone deacetylase 6 (HDAC6) selective inhibitors: A patent evaluation (WO2014181137). Expert Opin Ther Pat 2017; 27: 229-236
    CrossrefPubMedGoogle Scholar
  • 52 Amengual JE, Prabhu SA, Lombardo M. et al. Mechanisms of acquired drug resistance to the HDAC6 selective inhibitor ricolinostat reveals rational drug-drug combination with ibrutinib. Clin Cancer Res 2017; 23: 3084-3096
    CrossrefPubMedGoogle Scholar
  • 53 Lobera M, Madauss KP, Pohlhaus DT. et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol 2013; 9: 319-325
    CrossrefPubMedGoogle Scholar
  • 54 Wegener D, Wirsching F, Riester D. et al. A fluorogenic histone deacetylase assay well suited for high-throughput activity screening. Chem Biol 2003; 10: 61-68
    CrossrefPubMedGoogle Scholar