Nerve growth factor is a potent inducer of proliferation and neuronal differentiation for adult rat chromaffin cells in vitro

Abstract

Adult rat chromaffin cells in vitro show a large proliferative response to NGF, followed by neuronal differentiation. Infection of replicating chromaffin cells with a retrovirus carrying the Escherichia coli beta-galactosidase (beta-gal) gene demonstrates beta-gal expression in cells that continue to multiply, that differentiate into neurons, and that become static. The effects of NGF on proliferation and differentiation are abolished by the protein kinase inhibitors K252a and staurosporine, and by cholera toxin, an activator of adenylate cyclase. They are diminished, but not abolished, by high concentrations of dexamethasone. Both cholera toxin alone and phorbol myristate acetate (PMA), an activator of protein kinase C, elicit small and inconsistent mitogenic responses. The responses to PMA cannot be shown to be additive with the effects of NGF. NGF is a known mitogen and neuritogen for chromaffin cells from neonatal rats, but has not previously been believed to affect similarly chromaffin cells from adults. The present findings suggest that portions of NGF signaling pathways might continue to be involved in regulating proliferation of adult rat chromaffin cells in vivo, and might be constitutively activated in PC12 cells and other adrenal medullary tumors. They further suggest that rat chromaffin cells might be propagated in vitro to obtain large numbers of sympathetic neurons expressing normal or exogenous genes.

Insulin-like growth factors act synergistically withbasic fibroblast growth factor and nerve growth factor to promote chromaffincell proliferation.

“…Previous studies have shown that NGF and bFGF induce an initial mitogenic response in neonatal and adult rat chromaffin cells and rat PC12 cells that is followed by neuronal differentiation and growth arrest (8,9,11,12,48,49), whereas IGF-I and IGF-II stimulate proliferation of PC12 cells only and are not capable of inducing a neuronal phenotype (28,29). This is confirmed by ourfinding that IGFs did not induce neuronal differentiation of chromaffin cells in contrast to bFGF and NGF, suggesting that the signals leading to neuronal differentiation are different from those leading to cell division.…”

“…Postnatally, basic fibroblast growth factor (bFGF) is present in bovine and rat adrenal medulla (6,7), and bFGF stimulates the proliferation of neonatal rat chromaffmi cells (8,9). It is not known whether nerve growth factor (NGF) is present in the adrenal medulla, but specific high-affinity NGF binding sites have been demonstrated in chromaffnm cells from neonatal rats (10), and NGF acts as a mitogen on cultured chromaffm cells from neonatal and adult rats (11,12). In addition, NGF and bFGF stimulate transdifferentiation of cultured chromaffin cells into a sympathetic neuron-like phenotype and increase cell survival and catecholamine synthesis (8,9,(13)(14)(15).…”

Nuclear accumulation of fibroblast growth factor receptors is regulated by multiple signals in adrenal medullary cells.

“…These findings suggest that FGF-2 can serve as an intermediary in the neural regulation of adrenal medullary cells. Indeed, FGF-2 alters the expression of neurotransmitter biosynthetic genes in adrenal chromaffin cells (Puchacz et al, 1993), promotes transmitter storage and synthesis (Unsicker and Westermann, 1992), and stimulates the proliferation of cultured chromaffin cells (Stemple et al, 1988;Tischler et al, 1993;Frodin and Gammeltoft, 1994).…”

Low-Intensity Aerobic Exercise Mitigates Exercise-Induced Bronchoconstriction by Improving the Function of Adrenal Medullary Chromaffin Cells in Asthmatic Rats

“…NGF can promote the development of allergic inflammation and asthma via the mechanism of neurogenic inflammation (Nassenstein et al 2006). Moreover, NGF is a potent inducer of neuronal differentiation of rat chromaffin cells (Tischler et al 1993), which is negatively regulated by corticosterone (Unsicker et al 1978). In this study, we observed that low-or moderate-intensity aerobic exercise reduced the levels of serum NGF, but increased the levels of serum corticosterone, accompanied by inhibiting the neuronal transdifferentiation of AMCCs in asthmatic rats.…”

“…In addition, we found that high-intensity exercise not only promoted inflammatory responses and increased the airway resistance, but also induced neuronal transdifferentiation of AMCCs and subsequently decreased the levels of circulating epinephrine while moderate-intensity of exercise reversed these changes (He et al 2013). It is well known that nerve growth factor (NGF) is a potent inducer of neuronal differentiation of AMCCs while corticosterone stimulates the cells toward a neuroendocrine phenotype, playing an opposite role in regulating the transdifferentiation of AMCCs (Unsicker et al 1978(Unsicker et al , 1980Tischler et al 1993). However, our previous studies and those of others did not standardize exercise challenge and measure airway responsiveness to exercise, which might not well mimic the occurrence of EIB.…”