Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation.
OBJECTIVE
Glial progenitor cells are abundant in adult human white matter. This study was designed to identify signaling pathways regulating their self-renewal and fate.


METHODS
We compared the transcriptional profiles of freshly sorted adult human white matter progenitor cells (WMPCs), purified by A2B5-based immunomagnetic sorting, with those of the white matter from which they derived.


RESULTS
We identified 132 genes differentially expressed by WMPCs; these included principal components of five receptor-defined signaling pathways, represented by platelet derived growth factor receptor alpha (PDGFRA) and type 3 fibroblast growth factor receptor (FGFR3), receptor tyrosine phosphatase-beta/zeta (RTPZ), notch, and syndecan3. WMPCs also differentially expressed the bone morphogenetic protein 4 (BMP4) inhibitors neuralin and BAMBI (BMP and activin membrane-bound inhibitor), suggesting tonic defense against BMP signaling. Differential overexpression of RTPZ was accompanied by that of its modulators pleiotrophin, NrCAM, tenascin, and the chondroitin sulfate proteoglycans, suggesting the importance of RTPZ signaling to WMPCs. When exposed to the RTPZ inhibitor bpV(phen), or lentiviral-shRNAi against RTPZ, WMPCs differentiated as oligodendrocytes. Conversely, when neuralin and BAMBI were antagonized by BMP4, astrocytic differentiation was induced, which was reversible by noggin.


CONCLUSIONS
The RTPZ and BMP pathways regulate the self-maintenance of adult human WMPCs, and can be modulated to induce their oligodendrocytic or astrocytic differentiation. As such, they provide targets by which to productively mobilize resident progenitor cells of the adult human brain.
Sim
Fraser J
FJ
Department of Neurology, University of Rochester Medical Center, NY 14642, USA.
Lang
Jennifer K
JK
Waldau
Ben
B
Roy
Neeta S
NS
Schwartz
Theodore E
TE
Pilcher
Webster H
WH
Chandross
Karen J
KJ
Natesan
Sridaran
S
Merrill
Jean E
JE
Goldman
Steven A
SA
Goldmanm
Steven A
SA
D000293:Adolescent; D000328:Adult; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology; D004777:Environment; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009836:Oligodendroglia / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000187:drug effects; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D017027:Protein Tyrosine Phosphatases; D012313:RNA; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D000099176:Noggin Protein; C066845:pleiotrophin