Estradiol-17β-Induced Human Neural Progenitor Cell Proliferation Is Mediated by an Estrogen Receptor β-Phosphorylated Extracellularly Regulated Kinase Pathway

Abstract

Estradiol-17beta (E(2)) induces rodent hippocampal neural progenitor cell (NPC) proliferation in vitro, in vivo, and after brain injury. The purpose of the present investigation was to determine whether E(2)-induced proliferation observed in rodent model systems generalized to cells of human neural origin and the signaling pathway by which E(2) promotes mitosis of human NPCs (hNPCs). Results of these analyses indicate that E(2) induced a significant increase in hNPC proliferation in a time- and dose-dependent manner. E(2)-induced hNPC DNA replication was paralleled by elevated cell cycle protein expression and centrosome amplification, which was associated with augmentation of total cell number. To determine whether estrogen receptor (ER) and which ER subtype were required for E(2)-induced hNPC proliferation, ER expression was first determined by real-time RT-PCR, followed by Western blot analysis, and subsequently verified pharmacologically using ERalpha or beta-selective ligands. Results of these analyses indicated that ERbeta expression was predominant relative to ERalpha, which was barely detectable in hNPCs. Activation of ERbeta by the ERbeta-selective ligand, diarylpropionitrile, led to an increase in phosphorylated extracellular signal-regulated kinase, and subsequent centrosome amplification and hNPC proliferation, which were blocked by the MEKK antagonist, UO126, but not its inactive analog, UO124. These findings, for the first time, demonstrate the molecular cascade and related cell biology events involved in E(2)-induced hNPC proliferation in vitro. Therapeutic implications of these findings relevant to hormone therapy and prevention of neurodegenerative disease are discussed.

Effect of pregnancy on the proliferation of rat adipose-derived stem cells

“…Interestingly, the relationship between cell proliferation and estradiol is consistent with the results obtained with human neural progenitor cells, while this is not the case with progesterone. Wang et al (2008) found that E2 can induce human neural progenitor cell proliferation, which is mediated by an estrogen receptor beta-phosphorylated extracellularly regulated kinase pathway. The estrogen receptor is the decisive factor influencing cellular response to estrogen (Cobellis et al, 2002), and it was shown to exist in MSCs (Zhou et al, 2001;Wang et al, 2006).…”

Stem Cells with Neurogenic Potential and Steroid Hormones

“…Neuronal differentiation seems to be promoted by testosterone both in vitro and in vivo. The recent area of non-genomic effects of steroid hormones and the intersection with well-known intracellular pathways should provide important information related Increase in percentage of BrdU-labeled mature oligodendrocytes after injury To be determined [81] Rat and human NSC from fetal brain Increase in proliferation L-type voltage-gated calcium channels [83] Newborn rat neural progenitors Increase in proliferation GABAA receptor [84] Allopregnanolone Rat adult SVZ NSC Decrease in BrdU-labeled cells in the OB after intraventricular administration in vivo To be determined [85] Mouse and human pluripotent stem cells Increase in proliferation and neuronal differentiation; decrease in apoptosis To be determined [86] Human developing cerebral cortex NSC Increase in proliferation and neuronal differentiation Glutamate NMDA receptor in proliferative effect [88] Dehydroepiandrosterone Rat hippocampal NSC Increase in neurogenesis in vivo To be determined [89] Mouse ESC Increase in proliferation ER-and MAPKdependent [90] Rat developing striatal and adult SVZ NSC Increase in proliferation and neuronal differentiation ER-dependent [91] Mouse and human cerebrocortical neural precursors Increased proliferation ER and ERK [93,94] Mouse ESC-derived NSC Increase in proliferation of dopamine-comitted cells ER [95] Estradiol Mouse adult SVZ Increase in proliferation in vivo after ischemic insult ER and ER [101] Mouse ESC Increased proliferation AR [102] Androgens Cultured rat developing brain and adult neural precursors Increased proliferation, but antagonized EGF-induced proliferation. In fetal cells, increased neurogenesis.…”

“…ER are expressed in neural precursors from developing CNS: both receptors are present in mouse striatal [91] and human midbrain [92] NSC; other groups have reported a preferential expression of ER in mouse [93] or ER in human [94] cells. Estradiol promotes proliferation of striatal [91] and cortical cells of mouse [93] and human origin [94]; for both rodent and human cortical cells, such proliferative effects involved activation of ERK.…”

“…Estradiol promotes proliferation of striatal [91] and cortical cells of mouse [93] and human origin [94]; for both rodent and human cortical cells, such proliferative effects involved activation of ERK. Proliferative effects of this estrogen were also present in dopamine-committed neural precursors derived from mESC, resulting in higher proportions of terminally differentiated neurons [95].…”

Stroke in Women

“…Estrogen has anti-inflammatory effects via down regulation of glial activation, attenuation of nuclear factor kappa B activation, prevention of liposaccharide induced proinflammatory response decrease in release of superoxide anion from microglia and hydrogen peroxide production, thus limiting reactive oxygen species (ROS) mediated neuronal death following ischemic insult [176][177][178]. 17 Estradiol has been demonstrated to promote neurogenesis in rat brain, and promotes proliferation of neural progenitor cells in vitro [179][180][181].…”