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Cyclic AMP Signaling through Epac Axis Modulates Human Hemogenic Endothelium and Enhances Hematopoietic Cell Generation

Saxena, Shobhit LU ; Rönn, Roger E LU ; Guibentif, Carolina LU ; Moraghebi, Roksana LU and Woods, Niels-Bjarne LU (2016) In Stem Cell Reports 6(5). p.692-703
Abstract

Hematopoietic cells emerge from hemogenic endothelium in the developing embryo. Mechanisms behind human hematopoietic stem and progenitor cell development remain unclear. Using a human pluripotent stem cell differentiation model, we report that cyclic AMP (cAMP) induction dramatically increases HSC-like cell frequencies. We show that hematopoietic cell generation requires cAMP signaling through the Exchange proteins activated by cAMP (cAMP-Epac) axis; Epac signaling inhibition decreased both hemogenic and non-hemogenic endothelium, and abrogated hematopoietic cell generation. Furthermore, in hematopoietic progenitor and stem-like cells, cAMP induction mitigated oxidative stress, created a redox-state balance, and enhanced C-X-C... (More)

Hematopoietic cells emerge from hemogenic endothelium in the developing embryo. Mechanisms behind human hematopoietic stem and progenitor cell development remain unclear. Using a human pluripotent stem cell differentiation model, we report that cyclic AMP (cAMP) induction dramatically increases HSC-like cell frequencies. We show that hematopoietic cell generation requires cAMP signaling through the Exchange proteins activated by cAMP (cAMP-Epac) axis; Epac signaling inhibition decreased both hemogenic and non-hemogenic endothelium, and abrogated hematopoietic cell generation. Furthermore, in hematopoietic progenitor and stem-like cells, cAMP induction mitigated oxidative stress, created a redox-state balance, and enhanced C-X-C chemokine receptor type 4 (CXCR4) expression, benefiting the maintenance of these primitive cells. Collectively, our study provides insights and mechanistic details on the previously unrecognized role of cAMP signaling in regulating human hematopoietic development. These findings advance the mechanistic understanding of hematopoietic development toward the development of transplantable human hematopoietic cells for therapeutic needs.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Stem Cell Reports
volume
6
issue
5
pages
692 - 703
publisher
Cell Press
external identifiers
  • Scopus:84963971893
ISSN
2213-6711
DOI
10.1016/j.stemcr.2016.03.006
language
English
LU publication?
yes
id
a1869432-1ee8-44c4-a518-b5ef4e85f120
date added to LUP
2016-04-28 15:12:53
date last changed
2016-10-13 05:07:18
@misc{a1869432-1ee8-44c4-a518-b5ef4e85f120,
  abstract     = {<p>Hematopoietic cells emerge from hemogenic endothelium in the developing embryo. Mechanisms behind human hematopoietic stem and progenitor cell development remain unclear. Using a human pluripotent stem cell differentiation model, we report that cyclic AMP (cAMP) induction dramatically increases HSC-like cell frequencies. We show that hematopoietic cell generation requires cAMP signaling through the Exchange proteins activated by cAMP (cAMP-Epac) axis; Epac signaling inhibition decreased both hemogenic and non-hemogenic endothelium, and abrogated hematopoietic cell generation. Furthermore, in hematopoietic progenitor and stem-like cells, cAMP induction mitigated oxidative stress, created a redox-state balance, and enhanced C-X-C chemokine receptor type 4 (CXCR4) expression, benefiting the maintenance of these primitive cells. Collectively, our study provides insights and mechanistic details on the previously unrecognized role of cAMP signaling in regulating human hematopoietic development. These findings advance the mechanistic understanding of hematopoietic development toward the development of transplantable human hematopoietic cells for therapeutic needs.</p>},
  author       = {Saxena, Shobhit and Rönn, Roger E and Guibentif, Carolina and Moraghebi, Roksana and Woods, Niels-Bjarne},
  issn         = {2213-6711},
  language     = {eng},
  number       = {5},
  pages        = {692--703},
  publisher    = {ARRAY(0x88e9cf8)},
  series       = {Stem Cell Reports},
  title        = {Cyclic AMP Signaling through Epac Axis Modulates Human Hemogenic Endothelium and Enhances Hematopoietic Cell Generation},
  url          = {http://dx.doi.org/10.1016/j.stemcr.2016.03.006},
  volume       = {6},
  year         = {2016},
}