title: Serine protease inhibitor kunitz-type 2 is downregulated in myelodysplastic syndromes and modulates cell-cell adhesion.
abstract: Myelodysplastic syndromes (MDS) are clonal disorders involving hematopoietic stem cells (HSC) characterized by ineffective hematopoiesis. In addition to HSC defects, a defective hematopoiesis supporting capacity of mesenchymal stromal cells (MSCs) in the microenvironment niche has been implicated in MDS pathophysiology. The interaction between the dysfunctional MSCs MDS and HSC regulates diverse adhesion-related processes, such as progenitor cell survival, proliferation, differentiation, and self-renewal. As previously reported, a microarray analysis identified serine protease inhibitor kunitz-type 2 (SPINT2), an inhibitor of hepatocyte growth factor (HGF) activation, to be downregulated in MSCs from MDS patients. To define the role of SPINT2 in MDS hematopoietic microenvironment, an analysis of the effect of SPINT2 silencing in MSCs was carried out. We herein reported significantly lower levels of SPINT2 whereas HGF was expressed at higher levels in MSCs from MDS patients compared with healthy controls. SPINT2 underexpression results in an increased expression, production, and secretion of HGF and stromal cell-derived factor 1 (SDF-1) by MSCs. An increased adhesion of normal HSC or malignant cells onto MSCs silenced for SPINT2 was also observed. The altered MSCs adhesion in SPINT2-knockdown cells was correlated with increased CD49b and CD49d expression and with a decrease in CD49e expression. Our results suggest that the SPINT2 underexpression in the MSC from MDS patients is probably involved in the adhesion of progenitors to the bone marrow niche, through an increased HGF and SDF-1 signaling pathway.
authors.affiliation: 1 Instituto Nacional de Ciência e Tecnologia do Sangue, Hematology and Hemotherapy Center, University of Campinas/Hemocentro-Unicamp , Campinas, Brazil .
authors.forename: Fernanda Marconi
authors.initials: FM
authors.lastname: Roversi
authors.forename: Matheus Rodrigues
authors.initials: MR
authors.lastname: Lopes
authors.forename: João Agostinho
authors.initials: JA
authors.lastname: Machado-Neto
authors.forename: Ana Leda F
authors.initials: AL
authors.lastname: Longhini
authors.forename: Adriana da Silva Santos
authors.initials: Ada S
authors.lastname: Duarte
authors.forename: Mariana Ozello
authors.initials: MO
authors.lastname: Baratti
authors.forename: Bruna
authors.initials: B
authors.lastname: Palodetto
authors.forename: Flávia Adolfo
authors.initials: FA
authors.lastname: Corrocher
authors.forename: Fernando Vieira
authors.initials: FV
authors.lastname: Pericole
authors.forename: Paula de Melo
authors.initials: Pde M
authors.lastname: Campos
authors.forename: Patricia
authors.initials: P
authors.lastname: Favaro
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.forename: Sara Teresinha Olalla
authors.initials: ST
authors.lastname: Saad
mesh_terms: D000293:Adolescent; D000328:Adult; D002448:Cell Adhesion; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C066855:HGF protein, human; D039482:Integrin alpha5; D008562:Membrane Glycoproteins; C109148:SPINT2 protein, human; D017228:Hepatocyte Growth Factor