CXCL12 enhances human neural progenitor cell survival through a CXCR7- and CXCR4-mediated endocytotic signaling pathway

Bing Zhu, Dongsheng Xu, Xiaobei Deng, Qiang Chen, Yunlong Huang, Hui Peng, Yuju Li, Beibei Jia, Wallace B Thoreson, Wenjun Ding, Jianqing Ding, Lixia Zhao, Yi Wang, Kristin Leland Wavrin, Shumin Duan, Jialin C Zheng

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Chemokine CXCL12 is widely expressed in the central nervous system and essential for the proper functioning of human neural progenitor cells (hNPCs). Although CXCL12 is known to function through its receptor CXCR4, recent data have suggested that CXCL12 binds to chemokine receptor CXCR7 with higher affinity than to CXCR4. However, little is known about the function of CXCR7 in hNPCs. Using a primary hNPC culture system, we demonstrated that CXCL12 promotes hNPC survival in the events of camptothecin- induced apoptosis or growth factor deprivation, and that this effect requires both CXCR7 and CXCR4. Through fluorescence-activated cell sorting analysis and immunocytochemistry, we determined that CXCR7 is mainly localized in the early endosome, while CXCR4 is more broadly expressed at the cell surface and on both early and recycling endosomes. Furthermore, we found that endocytosis is required for the prosurvival function of CXCL12. Using dual-color total internal reflection fluorescence microscopy and immunoprecipitation, we demonstrated that CXCR7 quickly trafficks to plasma membrane in mediating CXCL12 endocytosis and colocalizes with CXCR4 after CXCL12 treatment. Investigating the molecular mechanisms, we found that ERK1/2 endocytotic signaling pathway is essential for hNPC survival upon apoptotic challenges. Consistent with these findings, a significantly higher number of apoptotic NPCs were found in the developing brain of CXCR7 knockout mice. In conclusion, CXCL12 protects hNPCs from apoptotic challenges through CXCR7- and CXCR4-mediated endocytotic signaling. Since survival of hNPCs is important for neurogenesis, CXCR7 may become a new therapeutic target to properly regulate critical processes of brain development.

Original languageEnglish (US)
Pages (from-to)2571-2583
Number of pages13
JournalSTEM CELLS
Volume30
Issue number11
DOIs
StatePublished - Nov 1 2012

Fingerprint

Cell Survival
Stem Cells
Endosomes
Endocytosis
CXCR4 Receptors
Chemokine CXCL12
Camptothecin
Chemokine Receptors
Neurogenesis
Brain
Fluorescence Microscopy
Immunoprecipitation
Knockout Mice
Intercellular Signaling Peptides and Proteins
Flow Cytometry
Central Nervous System
Color
Cell Culture Techniques
Immunohistochemistry
Cell Membrane

Keywords

  • Apoptosis
  • CXCR4
  • CXCR7
  • Neural stem cell

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

CXCL12 enhances human neural progenitor cell survival through a CXCR7- and CXCR4-mediated endocytotic signaling pathway. / Zhu, Bing; Xu, Dongsheng; Deng, Xiaobei; Chen, Qiang; Huang, Yunlong; Peng, Hui; Li, Yuju; Jia, Beibei; Thoreson, Wallace B; Ding, Wenjun; Ding, Jianqing; Zhao, Lixia; Wang, Yi; Wavrin, Kristin Leland; Duan, Shumin; Zheng, Jialin C.

In: STEM CELLS, Vol. 30, No. 11, 01.11.2012, p. 2571-2583.

Research output: Contribution to journalArticle

Zhu, B, Xu, D, Deng, X, Chen, Q, Huang, Y, Peng, H, Li, Y, Jia, B, Thoreson, WB, Ding, W, Ding, J, Zhao, L, Wang, Y, Wavrin, KL, Duan, S & Zheng, JC 2012, 'CXCL12 enhances human neural progenitor cell survival through a CXCR7- and CXCR4-mediated endocytotic signaling pathway', STEM CELLS, vol. 30, no. 11, pp. 2571-2583. https://doi.org/10.1002/stem.1239
Zhu, Bing ; Xu, Dongsheng ; Deng, Xiaobei ; Chen, Qiang ; Huang, Yunlong ; Peng, Hui ; Li, Yuju ; Jia, Beibei ; Thoreson, Wallace B ; Ding, Wenjun ; Ding, Jianqing ; Zhao, Lixia ; Wang, Yi ; Wavrin, Kristin Leland ; Duan, Shumin ; Zheng, Jialin C. / CXCL12 enhances human neural progenitor cell survival through a CXCR7- and CXCR4-mediated endocytotic signaling pathway. In: STEM CELLS. 2012 ; Vol. 30, No. 11. pp. 2571-2583.
@article{1c4dafa3cd4842f0bfc6425c2e571220,
title = "CXCL12 enhances human neural progenitor cell survival through a CXCR7- and CXCR4-mediated endocytotic signaling pathway",
abstract = "Chemokine CXCL12 is widely expressed in the central nervous system and essential for the proper functioning of human neural progenitor cells (hNPCs). Although CXCL12 is known to function through its receptor CXCR4, recent data have suggested that CXCL12 binds to chemokine receptor CXCR7 with higher affinity than to CXCR4. However, little is known about the function of CXCR7 in hNPCs. Using a primary hNPC culture system, we demonstrated that CXCL12 promotes hNPC survival in the events of camptothecin- induced apoptosis or growth factor deprivation, and that this effect requires both CXCR7 and CXCR4. Through fluorescence-activated cell sorting analysis and immunocytochemistry, we determined that CXCR7 is mainly localized in the early endosome, while CXCR4 is more broadly expressed at the cell surface and on both early and recycling endosomes. Furthermore, we found that endocytosis is required for the prosurvival function of CXCL12. Using dual-color total internal reflection fluorescence microscopy and immunoprecipitation, we demonstrated that CXCR7 quickly trafficks to plasma membrane in mediating CXCL12 endocytosis and colocalizes with CXCR4 after CXCL12 treatment. Investigating the molecular mechanisms, we found that ERK1/2 endocytotic signaling pathway is essential for hNPC survival upon apoptotic challenges. Consistent with these findings, a significantly higher number of apoptotic NPCs were found in the developing brain of CXCR7 knockout mice. In conclusion, CXCL12 protects hNPCs from apoptotic challenges through CXCR7- and CXCR4-mediated endocytotic signaling. Since survival of hNPCs is important for neurogenesis, CXCR7 may become a new therapeutic target to properly regulate critical processes of brain development.",
keywords = "Apoptosis, CXCR4, CXCR7, Neural stem cell",
author = "Bing Zhu and Dongsheng Xu and Xiaobei Deng and Qiang Chen and Yunlong Huang and Hui Peng and Yuju Li and Beibei Jia and Thoreson, {Wallace B} and Wenjun Ding and Jianqing Ding and Lixia Zhao and Yi Wang and Wavrin, {Kristin Leland} and Shumin Duan and Zheng, {Jialin C}",
year = "2012",
month = "11",
day = "1",
doi = "10.1002/stem.1239",
language = "English (US)",
volume = "30",
pages = "2571--2583",
journal = "Stem Cells",
issn = "1066-5099",
publisher = "AlphaMed Press",
number = "11",

}

TY - JOUR

T1 - CXCL12 enhances human neural progenitor cell survival through a CXCR7- and CXCR4-mediated endocytotic signaling pathway

AU - Zhu, Bing

AU - Xu, Dongsheng

AU - Deng, Xiaobei

AU - Chen, Qiang

AU - Huang, Yunlong

AU - Peng, Hui

AU - Li, Yuju

AU - Jia, Beibei

AU - Thoreson, Wallace B

AU - Ding, Wenjun

AU - Ding, Jianqing

AU - Zhao, Lixia

AU - Wang, Yi

AU - Wavrin, Kristin Leland

AU - Duan, Shumin

AU - Zheng, Jialin C

PY - 2012/11/1

Y1 - 2012/11/1

N2 - Chemokine CXCL12 is widely expressed in the central nervous system and essential for the proper functioning of human neural progenitor cells (hNPCs). Although CXCL12 is known to function through its receptor CXCR4, recent data have suggested that CXCL12 binds to chemokine receptor CXCR7 with higher affinity than to CXCR4. However, little is known about the function of CXCR7 in hNPCs. Using a primary hNPC culture system, we demonstrated that CXCL12 promotes hNPC survival in the events of camptothecin- induced apoptosis or growth factor deprivation, and that this effect requires both CXCR7 and CXCR4. Through fluorescence-activated cell sorting analysis and immunocytochemistry, we determined that CXCR7 is mainly localized in the early endosome, while CXCR4 is more broadly expressed at the cell surface and on both early and recycling endosomes. Furthermore, we found that endocytosis is required for the prosurvival function of CXCL12. Using dual-color total internal reflection fluorescence microscopy and immunoprecipitation, we demonstrated that CXCR7 quickly trafficks to plasma membrane in mediating CXCL12 endocytosis and colocalizes with CXCR4 after CXCL12 treatment. Investigating the molecular mechanisms, we found that ERK1/2 endocytotic signaling pathway is essential for hNPC survival upon apoptotic challenges. Consistent with these findings, a significantly higher number of apoptotic NPCs were found in the developing brain of CXCR7 knockout mice. In conclusion, CXCL12 protects hNPCs from apoptotic challenges through CXCR7- and CXCR4-mediated endocytotic signaling. Since survival of hNPCs is important for neurogenesis, CXCR7 may become a new therapeutic target to properly regulate critical processes of brain development.

AB - Chemokine CXCL12 is widely expressed in the central nervous system and essential for the proper functioning of human neural progenitor cells (hNPCs). Although CXCL12 is known to function through its receptor CXCR4, recent data have suggested that CXCL12 binds to chemokine receptor CXCR7 with higher affinity than to CXCR4. However, little is known about the function of CXCR7 in hNPCs. Using a primary hNPC culture system, we demonstrated that CXCL12 promotes hNPC survival in the events of camptothecin- induced apoptosis or growth factor deprivation, and that this effect requires both CXCR7 and CXCR4. Through fluorescence-activated cell sorting analysis and immunocytochemistry, we determined that CXCR7 is mainly localized in the early endosome, while CXCR4 is more broadly expressed at the cell surface and on both early and recycling endosomes. Furthermore, we found that endocytosis is required for the prosurvival function of CXCL12. Using dual-color total internal reflection fluorescence microscopy and immunoprecipitation, we demonstrated that CXCR7 quickly trafficks to plasma membrane in mediating CXCL12 endocytosis and colocalizes with CXCR4 after CXCL12 treatment. Investigating the molecular mechanisms, we found that ERK1/2 endocytotic signaling pathway is essential for hNPC survival upon apoptotic challenges. Consistent with these findings, a significantly higher number of apoptotic NPCs were found in the developing brain of CXCR7 knockout mice. In conclusion, CXCL12 protects hNPCs from apoptotic challenges through CXCR7- and CXCR4-mediated endocytotic signaling. Since survival of hNPCs is important for neurogenesis, CXCR7 may become a new therapeutic target to properly regulate critical processes of brain development.

KW - Apoptosis

KW - CXCR4

KW - CXCR7

KW - Neural stem cell

UR - http://www.scopus.com/inward/record.url?scp=84867917999&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867917999&partnerID=8YFLogxK

U2 - 10.1002/stem.1239

DO - 10.1002/stem.1239

M3 - Article

VL - 30

SP - 2571

EP - 2583

JO - Stem Cells

JF - Stem Cells

SN - 1066-5099

IS - 11

ER -