Mimicking the Neurotrophic Factor Profile of Embryonic Spinal Cord Controls the Differentiation Potential of Spinal Progenitors into Neuronal Cells

Abstract

Recent studies have indicated that the choice of lineage of neural progenitor cells is determined, at least in part, by environmental factors, such as neurotrophic factors. Despite extensive studies using exogenous neurotrophic factors, the effect of endogenous neurotrophic factors on the differentiation of progenitor cells remains obscure. Here we show that embryonic spinal cord derived-progenitor cells express both ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) mRNA before differentiation. BDNF gene expression significantly decreases with their differentiation into the specific lineage, whereas CNTF gene expression significantly increases. The temporal pattern of neurotrophic factor gene expression in progenitor cells is similar to that of the spinal cord during postnatal development. Approximately 50% of spinal progenitor cells differentiated into astrocytes. To determine the effect of endogenous CNTF on their differentiation, we neutralized endogenous CNTF by administration of its polyclonal antibody. Neutralization of endogenous CNTF inhibited the differentiation of progenitor cells into astrocytes, but did not affect the numbers of neurons or oligodendrocytes. Furthermore, to mimic the profile of neurotrophic factors in the spinal cord during embryonic development, we applied BDNF or neurotrophin (NT)-3 exogenously in combination with the anti-CNTF antibody. The exogenous application of BDNF or NT-3 promoted the differentiation of these cells into neurons or oligodendrocytes, respectively. These findings suggest that endogenous CNTF and exogenous BDNF and NT-3 play roles in the differentiation of embryonic spinal cord derived progenitor cells into astrocytes, neurons and oligodendrocytes, respectively.

Effect of BDNF and Other Potential Survival Factors in Models of In Vitro Oxidative Stress on Adult Spinal Cord–Derived Neural Stem/Progenitor Cells

“…We found that a 48 h pretreatment with 20 ng/mL BDNF did not alter NSPC proliferation compared with control. Our results are consistent with previous reports demonstrating that the same concentration of BDNF has no effect on the proliferation of embryonic-derived spinal cord progenitor cells 36 or brain-derived neural stem cells 37 even after seven days of treatment. While other studies report increased proliferation of neural stem cells treated with BDNF in combination with EGF compared with EGF treatment alone, these studies utilized either higher concentrations of BDNF or an extended treatment period.…”

An Activated Protein C Analog Stimulates Neuronal Production by Human Neural Progenitor Cells via a PAR1-PAR3-S1PR1-Akt Pathway

“…We also show that 3K3A-APC inhibits the development of astrocyte and oligodendrocyte lineages from human NPCs. In this regard, 3K3A-APC pro-neurogenic effects are similar to these of BDNF, which has been shown to promote neuronal differentiation of cultured NPCs (Goldman et al, 1997), while suppressing astrocyte differentiation (Nakamura et al, 2011). Since inflammatory mediators after CNS injury or diseases as well as NPCs transplantation promote astrogliosis but inhibit neurogenesis (Sahni and Kessler, 2010; Robel et al, 2011), the promoting effect on neuronal differentiation but inhibiting effect on astroglial differentiation and inflammation by 3K3A-APC would favorably support 3K3A-APC-related clinical trial for CNS repair.…”

Functions of neurotrophins and growth factors in neurogenesis and brain repair

“…Engraftment of NSC expressing NT‐3 in infarcted brains increased the number of cholinergic, GABAergic, and glutamatergic neurons (68); moreover, co‐transplantation of NSC and Schwan cells expressing NT‐3 promoted differentiation into serotoninergic neurons in rat injured spinal cord (63). NT‐3 also participates in the differentiation of oligodendrocytes (23, 57, 69, 70) from cortical multipotent cells, but not of primary culture of cortical oligodendrocyte progenitors, which differentiate only in response to stimulation by platelet‐derived growth factor (PDGF) (71).…”