title: Nitric oxide-induced murine hematopoietic stem cell fate involves multiple signaling proteins, gene expression, and redox modulation.
abstract: There are a growing number of reports showing the influence of redox modulation in cellular signaling. Although the regulation of hematopoiesis by reactive oxygen species (ROS) and reactive nitrogen species (RNS) has been described, their direct participation in the differentiation of hematopoietic stem cells (HSCs) remains unclear. In this work, the direct role of nitric oxide (NO(•)), a RNS, in the modulation of hematopoiesis was investigated using two sources of NO(•) , one produced by endothelial cells stimulated with carbachol in vitro and another using the NO(•)-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) in vivo. Two main NO(•) effects were observed: proliferation of HSCs-especially of the short-term HSCs-and its commitment and terminal differentiation to the myeloid lineage. NO(•)-induced proliferation was characterized by the increase in the number of cycling HSCs and hematopoietic progenitor cells positive to BrdU and Ki-67, upregulation of Notch-1, Cx43, PECAM-1, CaR, ERK1/2, Akt, p38, PKC, and c-Myc. NO(•)-induced HSCs differentiation was characterized by the increase in granulocytic-macrophage progenitors, granulocyte-macrophage colony forming units, mature myeloid cells, upregulation of PU.1, and C/EBPα genes concomitantly to the downregulation of GATA-3 and Ikz-3 genes, activation of Stat5 and downregulation of the other analyzed proteins mentioned above. Also, redox status modulation differed between proliferation and differentiation responses, which is likely associated with the transition of the proliferative to differentiation status. Our findings provide evidence of the role of NO(•) in inducing HSCs proliferation and myeloid differentiation involving multiple signaling.
authors: Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, Brasil.
authors: Amanda
authors: A
authors: Nogueira-Pedro
authors: Carolina C
authors: CC
authors: Dias
authors: Helena
authors: H
authors: Regina
authors: C
authors: C
authors: Segreto
authors: Priscilla C
authors: PC
authors: Addios
authors: Lisandro
authors: L
authors: Lungato
authors: Vania
authors: V
authors: D'Almeida
authors: Carlos C
authors: CC
authors: Barros
authors: Elisa M S
authors: EM
authors: Higa
authors: Marcus V
authors: MV
authors: Buri
authors: Alice T
authors: AT
authors: Ferreira
authors: Edgar Julian
authors: EJ
authors: Paredes-Gamero
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D019070:Cell Lineage; D049109:Cell Proliferation / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide
keywords: Bone marrow; Differentiation; Hematopoietic stem cells; Proliferation