Differentiation of Oligodendroglial Progenitors Derived from Cortical Multipotent Cells Requires Extrinsic Signals Including Activation of gp130/LIFβ Receptors

Abstract

We have previously isolated epidermal growth factor (EGF)-responsive multipotent progenitor cells from the early postnatal rodent cerebral cortex independent of generative zones. In this study we have examined the mechanisms regulating the generation of differentiated oligodendrocytes (OLs) from these multipotent cells. Although cultures of primary cortical OL progenitor cells propagated at clonal density spontaneously gave rise to differentiated OLs in defined medium, cultures of multipotent progenitors isolated from identical regions supported the elaboration of OL progenitors but not differentiated OLs. These observations indicate that the terminal maturation of OL progenitors derived from multipotent cells is dependent on signals present within the cellular environment. Application of cytokines such as basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), or neurotrophin 3 (NT3) to clonal density cultures of cortical multipotent progenitors increased the proportion of OL progenitors but failed to support the generation of differentiated OLs. By contrast, application of factors that activate gp130/leukemia inhibitory factor beta (LIFbeta) heterodimeric receptors, such as ciliary neurotrophic factor (CNTF), activated signal transducers and activators of transcription-3 in these OL progenitor cells and promoted the generation of differentiated OLs. Clonal analysis also demonstrated that CNTF directly targets OL progenitors derived from the multipotent cells. These observations suggest that two distinct progenitor cell pathways contribute to the generation of differentiated OLs during postnatal cortical gliogenesis. Although oligodendroglial maturation of classical OL progenitor cells is driven by cell autonomous mechanisms, our findings demonstrate that the generation of differentiated OLs from cortical multipotent progenitor cells is dependent on environmental cues, including activation of gp130/LIFbeta receptors.

Effects of defective herpes simplex vectors expressing neurotrophic factors on the proliferation and differentiation of nervous cells in vivo

“…It should be noted that these data relate either to peripheral preparations 26 or to CNS in vitro cell systems. 8,18,[21][22][23][24][25]27 Thus, the present one is the first evidence of a synergy between FGF-2 and CNTF occurring in the CNS in vivo.…”

“…These data support the notion that these two NTFs, when acting together, promote proliferation and glial differentiation. 8,18,21 However, depending on the experimental conditions, the developmental stage and the nervous system region, oligodendroglial 24,26 and neuronal 22,23,25,27 differentiation have also been reported. It should be noted that these data relate either to peripheral preparations 26 or to CNS in vitro cell systems.…”

“…8,18,21 Under specific experimental conditions, however, the combination of FGF-2 and CNTF has also been reported to promote oligodendroglial or neuronal differentiation. [22][23][24][25][26][27] Thus, it was expected that vectors expressing FGF-2 and CNTF would mimic this effect both in vitro and in the adult brain. Indeed, this proved to be the case.…”

Tumour formation by single fibroblast growth factor receptor 3-positive rhabdomyosarcoma-initiating cells

“…We tested bFGF, EGF, TGF-b1, CNTF, PDGF-AA, and PDGF-BB as candidates. These mitogens are important factors in maintaining many types of progenitor cells (Marmur et al, 1998;Kondo et al, 2004;Vallier and Pedersen, 2005). We first cultured unfractionated KYM-1 cells in serum-free culture medium alone or with a mixture of bFGF, EGF, TGF-b, CNTF, PDGF-AA, and PDGF-BB.…”

Neural stem cells in aging and disease

“…However, in both the developing and adult mouse CNS, activation of the gp130 receptor promotes gliogenesis through differentiation and/or survival of astrocytes [48][49][50]. The same factors can also promote the generation and survival of oligodendrocytes in vitro [51][52][53]. Thus, the effect of factors which affect NSCs and NPCs regulation must be considered in the context of the stage of development of the cell (ES cell vs. lineage restricted precursor).…”