Human neural progenitors express functional lysophospholipid receptors that regulate cell growth and morphology.
BACKGROUND
Lysophospholipids regulate the morphology and growth of neurons, neural cell lines, and neural progenitors. A stable human neural progenitor cell line is not currently available in which to study the role of lysophospholipids in human neural development. We recently established a stable, adherent human embryonic stem cell-derived neuroepithelial (hES-NEP) cell line which recapitulates morphological and phenotypic features of neural progenitor cells isolated from fetal tissue. The goal of this study was to determine if hES-NEP cells express functional lysophospholipid receptors, and if activation of these receptors mediates cellular responses critical for neural development.


RESULTS
Our results demonstrate that Lysophosphatidic Acid (LPA) and Sphingosine-1-phosphate (S1P) receptors are functionally expressed in hES-NEP cells and are coupled to multiple cellular signaling pathways. We have shown that transcript levels for S1P1 receptor increased significantly in the transition from embryonic stem cell to hES-NEP. hES-NEP cells express LPA and S1P receptors coupled to G i/o G-proteins that inhibit adenylyl cyclase and to G q-like phospholipase C activity. LPA and S1P also induce p44/42 ERK MAP kinase phosphorylation in these cells and stimulate cell proliferation via G i/o coupled receptors in an Epidermal Growth Factor Receptor (EGFR)- and ERK-dependent pathway. In contrast, LPA and S1P stimulate transient cell rounding and aggregation that is independent of EGFR and ERK, but dependent on the Rho effector p160 ROCK.


CONCLUSIONS
Thus, lysophospholipids regulate neural progenitor growth and morphology through distinct mechanisms. These findings establish human ES cell-derived NEP cells as a model system for studying the role of lysophospholipids in neural progenitors.
Hurst
Jillian H
JH
Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA, USA. jillhurst@gmail.com
Mumaw
Jennifer
J
Machacek
David W
DW
Sturkie
Carla
C
Callihan
Phillip
P
Stice
Steve L
SL
Hooks
Shelley B
SB
D002460:Cell Line; D049109:Cell Proliferation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D018715:Microscopy, Video; D046569:Neuroepithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism
D012333:RNA, Messenger; D049368:Receptors, Lysophosphatidic Acid; D049349:Receptors, Lysosphingolipid; D066246:ErbB Receptors; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins