Meis1 is a member of three-amino-acid loop extension (TALE) homeodomain transcription factors. Studies in the last decade have shown that Meis1 has crucial roles in cardiac regeneration, stem cell function, and tumorigenesis. We have recently demonstrated that knocking out of Meis1 in adult cardiomyocytes resulted in the induction of cardiomyocyte proliferation. This suggests that targeting of Meis1 might be utilized in the manipulation of cardiomyocyte cell cycle post cardiac injuries. In addition, hematopoietic stem cell (HSC) specific deletion of Meis1 leads to in vivo expansion of HSCs pool. Thus, targeting Meis1 may lead to not only cell cycle entry but also ex vivo and in vivo expansion of HSCs. On the other hand, Meis1 transcriptionally regulates the expression of hypoxic tumor markers, namely Hif-1α and Hif-2α. Hif-1α and Hif-2α are involved in the induction of cytoplasmic glycolysis and scavenging of reactive oxygen species (ROS), respectively. Studies highlight emerging roles of Meis1 towards development of new therapeutic approaches in the treatment of myocardial injuries, bone failure, and cancer (Reviewed in Current drug targets).
Development of MEIS inhibitors
We have performed a number of analysis to develop small molecule MEIS inhibitors, which includes but not limited to;
in silico drug screening
in vitro luciferase assays
PCR pathway analyses
ex vivo HSC expansion studies
in vivo HSC expansion studies
We have performed in silico screening of over 1 million small molecules which target MEIS homeodomain and are conducted in comparison to the other TALE homeodomains, have enabled to determine MEIS-specific hits
By means of the in vitro luciferase studies conducted, the MEIS inhibitors which we have named as MEIS inhibitor-1 (MEISi-1) and MEIS inhibitor-2 (MEISi-2) were determined for the first time. These inhibitors (MEISi-1 and MEISi-2) inhibit MEIS luciferase reporter (Mahmoud &Kocabas et al, Nature, 2012) in a dose-dependent manner.
It was found that MEISi-1 and MEISi-2, which are among the developed MEIS inhibitors, reduce expression of p21, Hif-1alpha (Hif-1α), Hif-2alpha (Hif-2α) genes in the Meis1 pathway.
Up to 2.5 times dose-dependent increase was determined in the number of hematopoietic cells treated with MEISi-1 and MEISi-2 after 10 days. In treatment with MEISi-1, up to 10 times increase was observed in the number of HSCs. This increase is dependent on the dose. In addition, in Lin- cells treated with MEISi-2, up to 3 times increase was observed in the number of HSCs.
It is observed from the increasing number of CFU-GEMM colonies that application of MEIS inhibitors increases the number of HSCs. MEIS inhibitors effectively enable functional increase of the HSCs.
When all of the results are analyzed, it is observed that MEIS inhibitors trigger functional ex vivo proliferation of human HSCs. When MEISi-1 and MEISi-2 were applied, CD34+ HSC number, CD133+ HSC number, CD34+CD133 HSC number and ALDHBr HSC number in human hematopoietic cell culture increased 2 times in comparison to DMSO control group.
It was demonstrated that in vivo application of MEISi-1 and MEISi-2 successfully increased HSC number in mouse bone marrow (LSKCD34low cells) and HSC number in the blood (LSKCD150+CD48- cells).
In short, it was observed that MEIS inhibitors realized functional ex vivo proliferation of mouse and human HSCs.
As a result, MEIS inhibitors were determined for the first time in the studies conducted. (Kocabas et al. Development of Small Molecule MEIS Inhibitors that Induce HSC Proliferation. Under review)
MEIS related awards, funds and publications
Poster Award. Fatih Kocabas, Ahmed I Mahmoud, Shalini Muralidhar, Suwannee Thet, Enzo R. Porrello, Eric Olson, and Hesham A. Sadek. Meis1 is a key regulator of post-natal cardiomyocyte cell cycle arrest. Basic Cardiovascular Sciences 2012 Scientific Sessions, New Orleans, Louisiana, USA (July 23-26, 2012). Circulation Research. 111(4_MeetingAbstracts) Supplement 1, July 20, 2012. [Award winning Abstract] [Circulation Research Impact Factor: 9.489]
Oral Presentation Award. Biruni University, Computer Aided Drug Design Meeting. May 2016.
Best poster award. October 2015.2nd International Congress of Stem Cell and Cellular Therapies. Antalya
Oral Presentation Award. MEMBS 2015 Congress awarded Dr. Kocabas for his talk titled "Small Molecule Induced Hematopoietic Stem Cell Expansion".
Funding: TUBITAK ARDEB 3501 Career Development. 2016-2018. Identification of Cardiogenic Meis1 Inhibitors
Funding: Turkish Society of Hematology (Türk Hematoloji Derneği) Research Award. 2016-2017. Ex vivo Hematopoietik Kök Hücre (HKH) çoğaltılmasında etkili Meis1 inhibitörlerinin araştırılması.
MEIS and MEISi related publications and talks
Fatih Kocabas (co-first author), Ahmed I Mahmoud, Shalini A. Muralidhar, Wataru Kimura, Ahmed S. Koura, Suwannee Thet, Enzo R. Porrello, and Hesham A. Sadek. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 497, no. 7448 (2013): 249-253. [Nature Impact Factor: 42.351] PDF
Fatih Kocabas, Junke Zheng, Suwannee Thet, Neal G. Copeland, Nancy A. Jenkins, Ralph J. DeBerardinis, Chengcheng Zhang, and Hesham A. Sadek. "Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells." Blood (2012). [Blood Impact Factor: 9.898] PDF
Fatih Kocabas(co-first author), Tugba Simsek, Junke Zheng, Ralph J. DeBerardinis, Ahmed I. Mahmoud, Eric N. Olson, Jay W. Schneider, Cheng Cheng Zhang, and Hesham A. Sadek. "The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche." Cell Stem Cell 7, no. 3 (2010): 380-390. [Cell Stem Cell Impact Factor: 25.421] PDF
Merve Aksoz, Raife Dilek Turan, Esra Albayrak, Fatih Kocabaş*. Emerging Roles of Meis1 in Cardiac Regeneration, Stem Cells, and Cancer. Current drug targets. 2017 Jul 24. doi: 10.2174/1389450118666170724165514 Full text
Fatih Kocabas*. Emerging Roles of MEIS1 in Hematopoiesis and Heart Regeneration.ISBN 978-3-659-59658-2. LAP LAMBERT Academic Publishing, Germany. February 23, 2015. Link
Fatih Kocabas*. MEIS1: At the Crossroads between Metabolic and Cell Cycle Regulation. PhD diss., 2013. UT Southwestern Electronic Theses and Dissertations. PDF
Şeyma Nur Eren, Raife Dilek Turan, Fatih Kocabaş. Hücre ekspansiyonunda etkin MEIS inhibitorlerinin geliştirilmesi. Hücresel İmmunoterapi sempozyumu. 20-22 October 2017. Trabzon, Turkey
Semih Arbatlı, Raife Dilek Turan, Galip Servet Aslan, Esra Albayrak, Serdar Durdağı, Fatih Kocabaş. Identification of Cardiogenic and Hematopoietic MEIS Inhibitors that Enhance Cellular Proliferation and HDR Gene Expression. 5th International Bau Drug Design Congress. 19-21 October, 2017. Istanbul, Turkey
Semih Arbatlı, Merve Uslu, Fatih Kocabaş. Identification of Cas9 small molecule inhibitors.Identification of Cardiogenic and Hematopoietic MEIS Inhibitors that Enhance Cellular Proliferation and HDR Gene Expression. 5th International Bau Drug Design Congress. 19-21 October, 2017. Istanbul, Turkey
Fatih Kocabaş, Semih Arbatlı, Raife Dilek Turan, Galip Servet Aslan, Esra Albayrak, Merve Uslu, Serdar Durdağı, Zafer Gülbaş. Identification of Hematopoietic and Cardiogenic MEIS Inhibitors that Enhance Cellular Proliferation and HDR Gene Expression. 5th International Congress of the Molecular Biology Association of Turkey (MolBiyoKon’17). 8-10 September 2017. Istanbul, Turkey
Raife Dilek Turan, Enes K. Ergin, Fatih Kocabas. The Establishment of Homeobox Family Inhibitor Library and Meis1 Reporter Assays. 3rd International BAU Drug Design Congress. Oct 1-3. 2015. Istanbul.
Fatih Kocabas, Ahmed I Mahmoud, Shalini Muralidhar, Suwannee Thet, Enzo R. Porrello, Eric Olson, and Hesham A. Sadek. Meis1 is a key regulator of post-natal cardiomyocyte cell cycle arrest. Basic Cardiovascular Sciences 2012 Scientific Sessions, New Orleans, Louisiana, USA (July 23-26, 2012). Circulation Research. 111(4_MeetingAbstracts) Supplement 1, July 20, 2012. [Award winning Abstract] [Circulation Research Impact Factor: 9.489]