Abstract
Exchange protein activated by cAMP-1 (Epac1) plays an important role in cell proliferation, cell survival and neuronal signaling, and activation of Epac1 in endothelial progenitor cells increases their homing to ischemic muscles and promotes neovascularization in a model of hind limb ischemia. Moreover, upregulation of Epac1 occurs during organ development and in diseases such as myocardial hypertrophy, diabetes, and Alzheimer's disease. We report here that hypoxia upregulated Epac1 through HIF-1α induction in the CD34-immunosorted human umbilical cord blood hematopoietic stem cells (hUCB34). Importantly, implantation of hUCB34 subjected to hypoxia-preconditioning (HP-hUCB34) improved stroke outcome, more than did implantation of untreated hUCB34, in rodents subjected to cerebral ischemia, and this required Epac1-to-matrix metalloprotease (MMP) signaling. This improved therapeutic efficacy correlated with better engraftment and differentiation of these cells in the ischemic host brain. In addition, more than did implantation of untreated HP-hUCB34, implantation of HP-hUCB34 improved cerebral blood flow into the ischemic brain via induction of angiogenesis, facilitated proliferation/recruitment of endogenous neural progenitor cells in the ischemic brain, and promoted neurite outgrowth following cerebral ischemia. Consistent with our proposed role of Epac1-to-MMP signaling in hypoxia-preconditioning, the above mentioned effects of implanting HP-hUCB34 could be abolished by pharmacological inhibition and genetic disruption/deletion of Epac1 or MMPs. We have discovered a HIF-1α-to-Epac1-to-MMP signaling pathway that is required for the improved therapeutic efficacy resulting from hypoxia preconditioning of hUCB34 in vitro prior to their implantation into the host brain in vivo.
| Original language | English |
|---|---|
| Pages (from-to) | 76-91 |
| Number of pages | 16 |
| Journal | Neurobiology of Disease |
| Volume | 58 |
| DOIs | |
| Publication status | Published - 2013 Oct |
| Externally published | Yes |
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Keywords
- Cerebral ischemia
- Epac1
- HUCB
- Hypoxia preconditioning (HP)
- Immunoselection of CD34
ASJC Scopus subject areas
- Neurology
Cite this
Role of HIF-1α-activated Epac1 on HSC-mediated neuroplasticity in stroke model. / Lin, Chen Huan; Lee, Hsu Tung; Lee, Shin Da; Lee, Wei; Cho, Chin Wen Chental; Lin, Shinn Zong; Wang, Hsiao Jung; Okano, Hideyuki; Su, Ching Yuan; Yu, Yung Luen; Hsu, Chung Y.; Shyu, Woei Cherng.
In: Neurobiology of Disease, Vol. 58, 10.2013, p. 76-91.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Role of HIF-1α-activated Epac1 on HSC-mediated neuroplasticity in stroke model
AU - Lin, Chen Huan
AU - Lee, Hsu Tung
AU - Lee, Shin Da
AU - Lee, Wei
AU - Cho, Chin Wen Chental
AU - Lin, Shinn Zong
AU - Wang, Hsiao Jung
AU - Okano, Hideyuki
AU - Su, Ching Yuan
AU - Yu, Yung Luen
AU - Hsu, Chung Y.
AU - Shyu, Woei Cherng
PY - 2013/10
Y1 - 2013/10
N2 - Exchange protein activated by cAMP-1 (Epac1) plays an important role in cell proliferation, cell survival and neuronal signaling, and activation of Epac1 in endothelial progenitor cells increases their homing to ischemic muscles and promotes neovascularization in a model of hind limb ischemia. Moreover, upregulation of Epac1 occurs during organ development and in diseases such as myocardial hypertrophy, diabetes, and Alzheimer's disease. We report here that hypoxia upregulated Epac1 through HIF-1α induction in the CD34-immunosorted human umbilical cord blood hematopoietic stem cells (hUCB34). Importantly, implantation of hUCB34 subjected to hypoxia-preconditioning (HP-hUCB34) improved stroke outcome, more than did implantation of untreated hUCB34, in rodents subjected to cerebral ischemia, and this required Epac1-to-matrix metalloprotease (MMP) signaling. This improved therapeutic efficacy correlated with better engraftment and differentiation of these cells in the ischemic host brain. In addition, more than did implantation of untreated HP-hUCB34, implantation of HP-hUCB34 improved cerebral blood flow into the ischemic brain via induction of angiogenesis, facilitated proliferation/recruitment of endogenous neural progenitor cells in the ischemic brain, and promoted neurite outgrowth following cerebral ischemia. Consistent with our proposed role of Epac1-to-MMP signaling in hypoxia-preconditioning, the above mentioned effects of implanting HP-hUCB34 could be abolished by pharmacological inhibition and genetic disruption/deletion of Epac1 or MMPs. We have discovered a HIF-1α-to-Epac1-to-MMP signaling pathway that is required for the improved therapeutic efficacy resulting from hypoxia preconditioning of hUCB34 in vitro prior to their implantation into the host brain in vivo.
AB - Exchange protein activated by cAMP-1 (Epac1) plays an important role in cell proliferation, cell survival and neuronal signaling, and activation of Epac1 in endothelial progenitor cells increases their homing to ischemic muscles and promotes neovascularization in a model of hind limb ischemia. Moreover, upregulation of Epac1 occurs during organ development and in diseases such as myocardial hypertrophy, diabetes, and Alzheimer's disease. We report here that hypoxia upregulated Epac1 through HIF-1α induction in the CD34-immunosorted human umbilical cord blood hematopoietic stem cells (hUCB34). Importantly, implantation of hUCB34 subjected to hypoxia-preconditioning (HP-hUCB34) improved stroke outcome, more than did implantation of untreated hUCB34, in rodents subjected to cerebral ischemia, and this required Epac1-to-matrix metalloprotease (MMP) signaling. This improved therapeutic efficacy correlated with better engraftment and differentiation of these cells in the ischemic host brain. In addition, more than did implantation of untreated HP-hUCB34, implantation of HP-hUCB34 improved cerebral blood flow into the ischemic brain via induction of angiogenesis, facilitated proliferation/recruitment of endogenous neural progenitor cells in the ischemic brain, and promoted neurite outgrowth following cerebral ischemia. Consistent with our proposed role of Epac1-to-MMP signaling in hypoxia-preconditioning, the above mentioned effects of implanting HP-hUCB34 could be abolished by pharmacological inhibition and genetic disruption/deletion of Epac1 or MMPs. We have discovered a HIF-1α-to-Epac1-to-MMP signaling pathway that is required for the improved therapeutic efficacy resulting from hypoxia preconditioning of hUCB34 in vitro prior to their implantation into the host brain in vivo.
KW - Cerebral ischemia
KW - Epac1
KW - HUCB
KW - Hypoxia preconditioning (HP)
KW - Immunoselection of CD34
UR - http://www.scopus.com/inward/record.url?scp=84879387756&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879387756&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2013.05.006
DO - 10.1016/j.nbd.2013.05.006
M3 - Article
C2 - 23702312
AN - SCOPUS:84879387756
VL - 58
SP - 76
EP - 91
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -