Transglutaminase Type 2 is Involved in the Hematopoietic Stem Cells Homeostasis
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Transglutaminase Type 2 is Involved in the Hematopoietic Stem Cells Homeostasis S. Oliverio1#, J. S. O. Beltran1,2#, L. Occhigrossi1, V. Bordoni3, C. Agrati3, M. D’Eletto1, F. Rossin1, P. Borelli2, G. P. AmaranteMendes4, O. Demidov5, N. A. Barlev5, and M. Piacentini1,3,5,a* 1
Department of Biology, University of Rome “Tor Vergata”, 00133 Rome, Italy Clinical and Experimental Hematology Laboratory, Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil 3 National Institute for Infectious Diseases I. R. C. C. S. “Lazzaro Spallanzani” 00149 Rome, Italy 4 Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil 5 Laboratory of Molecular Medicine, Institute of Cytology, Russian Academy of Sciences, 194064 St.Petersburg, Russia a email: [email protected] 2
Received July 9, 2020 Revised July 21, 2020 Accepted July 21, 2020 Abstract—Type 2 transglutaminase (TG2) is a multifunctional protein involved in various biological processes playing a key regulatory role in cell homeostasis such as cell death and autophagy. New evidence is emerging that support an important role of autophagy in regulating normal hematopoiesis. Prompted by these findings, in this study we investigated in vivo involvement of TG2 in mouse hematopoiesis under normal or nutrient deprivation conditions. We found that the number and rate of differentiation of bone marrow hematopoietic stem cell was decreased in the TG2 knockout mice. We present evidence showing that these effects on hematopoietic system are very likely due to the TG2dependent impairment of autophagy. In fact, stimulation of autophagy by starvation is able to rescue the block of the differentiation of stem cells pro genitors in the TG2 KO mice. It was also shown that the RhoA/ERK1/2 pathway, known to be essential for regulation of the bone marrow progenitor cells homeostasis, was significantly impaired in the absence of TG2. Hence, this study expand ed our knowledge about TG2 discovering a role of this enzyme in regulation of hematopoiesis. DOI: 10.1134/S0006297920100041 Keywords: TG2, hematopoietic stem cells, autophagy
INTRODUCTION Hematopoietic system develops from the multipo tent hematopoietic stem cells (HSCs). Major characteris tic of HSCs is their ability for selfrenewal to preserve a pool of undifferentiated cells able to mature into different blood cell types depending on the need of the body [1]. HSCs constitute a heterogeneous population and can be Abbreviations: BM, bone marrow; CFU, colonyforming units; HSC, hematopoietic stem cells; LTHSC and STHSC, long term and shortterm HSC; KO, TG2 knockout mice; LK, Lin– cKit+ hematopoietic cells enriched with myeloid and megakaryocyteerythroid progenitors; LSK, Lin– cKit+ Sca 1+ hematopoietic cells containing LTHSC, STHSC, and MPP; MPP, multipotent progenitors; PHSC, progenitor HSC; TG2, transglutaminase type 2; WT, wild type mice. * To whom correspondence should be addressed. # These a
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