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Autocrine/Paracrine Platelet-Derived Growth Factor Regulates Proliferation of Neural Progenitor Cells

¹ Department of Medical Biochemistry and Microbiology, Uppsala University; and ² Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden

Requests for reprints: Karin Forsberg-Nilsson, Department of Medical Biochemistry and Microbiology, Uppsala University, Box 582, 751 23 Uppsala, Sweden. Phone: 46-18-471-41-58; Fax: 46-18-471-42-44; E-mail: karin.nilsson{at}imbim.uu.se.

Growth factors play an important role in regulating neural stem cell proliferation and differentiation. This study shows that platelet-derived growth factor (PDGF) induces a partial differentiation of neural stem/progenitor cells (NSPCs) in the absence of other mitogens in vitro. NSPCs thus acquire an immature morphology and display markers for both neurons and glia. In addition, these cells do not readily mature in the absence of further stimuli. When NSPC cultures treated with PDGF were exposed to additional differentiation factors, however, the differentiation proceeded into neurons, astrocytes, and oligodendrocytes. We find that NSPC cultures are endowed with an endogenous PDGF-BB production. The PDGF-BB expression peaks during early differentiation and is present both in cell lysates and in conditioned medium, allowing for autocrine as well as paracrine signaling. When the NSPC-derived PDGF was inhibited, progenitor cell numbers decreased, showing that PDGF is involved in NSPC expansion. Addition of a PDGF receptor (PDGFR) inhibitor resulted in a more rapid differentiation. Neurons and oligodendrocytes appeared earlier and had more elaborate processes than in control cultures where endogenous PDGFR signaling was not blocked. Our observations point to PDGF as an inducer of partial differentiation of NSPC that also sustains progenitor cell division. Such an intermediate stage in stem cell differentiation is of relevance for the understanding of brain tumor development because autocrine PDGF stimulation is believed to drive malignant conversion of central nervous system progenitor cells. (Cancer Res 2006; 66(16): 8042-8)

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