Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells

Ishikawa, Eri Taniguchi and Gonzalez Nieto, Daniel and Ghiaur, Gabriel and Dunn, Susan K. and Ficker, Ashley M. and Murali, Bhuvana and Madhu, Malav and Gutstein, David E. and Fishman, Glenn I. and Barrio, Luis C. and Cancelas Pérez, José A. (2012). Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. "Proceedings of the National Academy of Sciences of the United States of America", v. 109 (n. 23); pp. 9071-9091. ISSN 0027-8424. https://doi.org/10.1073/pnas.1120358109.

Description

Title: Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells
Author/s:
  • Ishikawa, Eri Taniguchi
  • Gonzalez Nieto, Daniel
  • Ghiaur, Gabriel
  • Dunn, Susan K.
  • Ficker, Ashley M.
  • Murali, Bhuvana
  • Madhu, Malav
  • Gutstein, David E.
  • Fishman, Glenn I.
  • Barrio, Luis C.
  • Cancelas Pérez, José A.
Item Type: Article
Título de Revista/Publicación: Proceedings of the National Academy of Sciences of the United States of America
Date: July 2012
ISSN: 0027-8424
Volume: 109
Subjects:
Faculty: E.T.S.I. Telecomunicación (UPM)
Department: Tecnología Fotónica [hasta 2014]
Creative Commons Licenses: Recognition - No derivative works - Non commercial

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Abstract

Hematopoietic stem cell (HSC) aging has become a concern in chemotherapy of older patients. Humoral and paracrine signals from the bone marrow (BM) hematopoietic microenvironment (HM) control HSC activity during regenerative hematopoiesis. Connexin-43 (Cx43), a connexin constituent of gap junctions (GJs) is expressed in HSCs, down-regulated during differentiation, and postulated to be a self-renewal gene. Our studies, however, reveal that hematopoietic-specific Cx43 deficiency does not result in significant long-term competitive repopulation deficiency. Instead, hematopoietic Cx43 (H-Cx43) deficiency delays hematopoietic recovery after myeloablation with 5-fluorouracil (5-FU). 5-FU-treated H-Cx43-deficient HSC and progenitors (HSC/P) cells display decreased survival and fail to enter the cell cycle to proliferate. Cell cycle quiescence is associated with down-regulation of cyclin D1, up-regulation of the cyclin-dependent kinase inhibitors, p21cip1. and p16INK4a, and Forkhead transcriptional factor 1 (Foxo1), and activation of p38 mitogen-activated protein kinase (MAPK), indicating that H-Cx43-deficient HSCs are prone to senescence. The mechanism of increased senescence in H-Cx43-deficient HSC/P cells depends on their inability to transfer reactive oxygen species (ROS) to the HM, leading to accumulation of ROS within HSCs. In vivo antioxidant administration prevents the defective hematopoietic regeneration, as well as exogenous expression of Cx43 in HSC/P cells. Furthermore, ROS transfer from HSC/P cells to BM stromal cells is also rescued by reexpression of Cx43 in HSC/P. Finally, the deficiency of Cx43 in the HM phenocopies the hematopoietic defect in vivo. These results indicate that Cx43 exerts a protective role and regulates the HSC/P ROS content through ROS transfer to the HM, resulting in HSC protection during stress hematopoietic regeneration.

More information

Item ID: 19829
DC Identifier: http://oa.upm.es/19829/
OAI Identifier: oai:oa.upm.es:19829
DOI: 10.1073/pnas.1120358109
Official URL: http://www.pnas.org/content/early/2012/05/17/1120358109
Deposited by: Memoria Investigacion
Deposited on: 21 Sep 2013 08:54
Last Modified: 21 Apr 2016 21:25
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