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

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.

Intrapancreatic MSC transplantation facilitates pancreatic islet regeneration

“…Recently, embryonic, induced pluripotent, and mesenchymal stem cells have been employed to replace β cells [28][29][30][31][32][33][34]. Administration of MSC is advantageous over other stem cells as they ward off the risk of teratoma formation for the recipient [35][36][37]. In our study, ADMSC were transplanted subcutaneously into NMRI nude mice and observed for 42 days to exclude tumor formation (data not shown).…”

In vitro and in vivo anti−Toxoplasma activities of HDAC inhibitor Panobinostat on experimental acute ocular toxoplasmosis

“…The previous research has shown that anti- T. gondii effect of several HDAC inhibitors such as scriptaid, tubastatin A and suberoylanilide hydroxamic acid in HFF cells ( Araujo-Silva et al., 2021 ). In our study, we have evaluated the anti- T. gondii and therapeutic effect of LBH589 on OT for the first time, which was mainly used in cutaneous T-cell lymphoma (CTCL), Hodgkin’s lymphoma as well as acute myeloid leukemia (AML) in preclinical research ( Prince et al., 2009 ; Schroder et al., 2021 ; Chen et al., 2022 ). According to the pathogenesis of OT, retinal pigment epithelium has been identified to be the primary target for T. gondii infection within the eye ( Smith et al., 2021 ).…”

The Roles of Epigenetics Regulation in Bone Metabolism and Osteoporosis

“…These HDAC antagonists include trichostatin (TSA), suberoylanilide hydroxamic acid (SAHA), entenol (MS-275), sodium butyrate and valproic acid. In vitro experiments showed that blocking class I and class II HDACs at the same time or blocking class I HDACs alone could promote osteoblast maturation, bone mineralization and the expression of genes related to osteoblast differentiation and maturation, such as type I collagen, osteopontin (OPN), OCN, ALP, OSX, and RUNX2 (Schroeder and Westendorf, 2005;Schroeder et al, 2007;Schröder et al, 2020). Interestingly, TSAmediated acetylation of histones H4 and H3 in the RANKL promoter region resulted in increased expression of RANKL (Fan et al, 2004).…”