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

Eri Taniguchi Ishikawa, Daniel Gonzalez-Nieto, Gabriel Ghiaur, Susan K. Dunn, Ashley M. Ficker, Bhuvana Murali, Malav Madhu, David E. Gutstein, Glenn I. Fishman, Luis C. Barrio, Jose A. Cancelas

Research output: Contribution to journalArticle

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-FUtreated 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.

Original languageEnglish (US)
Pages (from-to)9071-9076
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number23
DOIs
StatePublished - Jun 5 2012
Externally publishedYes

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Connexin 43
Cell Aging
Hematopoietic Stem Cells
Mesenchymal Stromal Cells
Reactive Oxygen Species
Regeneration
Cell Cycle
Connexins
Cytoprotection
Cyclin-Dependent Kinases
Gap Junctions
Cyclin D1
Hematopoiesis
p38 Mitogen-Activated Protein Kinases
Fluorouracil
Up-Regulation
Stem Cells
Down-Regulation
Antioxidants
Bone Marrow

Keywords

  • Gja1
  • Stem cell niche

ASJC Scopus subject areas

  • General

Cite this

Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. / 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, Jose A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 23, 05.06.2012, p. 9071-9076.

Research output: Contribution to journalArticle

Ishikawa, ET, Gonzalez-Nieto, D, Ghiaur, G, Dunn, SK, Ficker, AM, Murali, B, Madhu, M, Gutstein, DE, Fishman, GI, Barrio, LC & Cancelas, JA 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, vol. 109, no. 23, pp. 9071-9076. https://doi.org/10.1073/pnas.1120358109
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, Jose A. / Connexin-43 prevents hematopoietic stem cell senescence through transfer of reactive oxygen species to bone marrow stromal cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 23. pp. 9071-9076.
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AU - Gonzalez-Nieto, Daniel

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AU - Dunn, Susan K.

AU - Ficker, Ashley M.

AU - Murali, Bhuvana

AU - Madhu, Malav

AU - Gutstein, David E.

AU - Fishman, Glenn I.

AU - Barrio, Luis C.

AU - Cancelas, Jose A.

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AB - 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-FUtreated 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.

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