Enhanced Neural Progenitor/Stem Cells Self‐Renewal via the Interaction of Stress‐Inducible Protein 1 with the Prion Protein

Abstract

Prion protein (PrP C ), when associated with the secreted form of the stress-inducible protein 1 (STI1), plays an important role in neural survival, neuritogenesis, and memory formation. However, the role of the PrP C -STI1 complex in the physiology of neural progenitor/stem cells is unknown. In this article, we observed that neurospheres cultured from fetal forebrain of wild-type (Prnp 1/1 ) and PrP C -null (Prnp 0/0 ) mice were maintained for several passages without the loss of self-renewal or multipotentiality, as assessed by their continued capacity to generate neurons, astrocytes, and oligodendrocytes. The homogeneous expression and colocalization of STI1 and PrP C suggest that they may associate and function as a complex in neurosphere-derived stem cells. The formation of neurospheres from Prnp 0/0 mice was reduced significantly when compared with their wild-type counterparts. In addition, blockade of secreted STI1, and its cell surface ligand, PrP C , with specific antibodies, impaired Prnp 1/1 neurosphere formation without further impairing the formation of Prnp 0/0 neurospheres. Alternatively, neurosphere formation was enhanced by recombinant STI1 application in cells expressing PrP C but not in cells from Prnp 0/0 mice. The STI1-PrP C interaction was able to stimulate cell proliferation in the neurosphere-forming assay, while no effect on cell survival or the expression of neural markers was observed. These data suggest that the STI1-PrP C complex may play a critical role in neural progenitor/stem cells self-renewal via the modulation of cell proliferation, leading to the control of the stemness capacity of these cells during nervous system development.

The cellular form of the prion protein guides the differentiation of human embryonic stem cells into neuron-, oligodendrocyte-, and astrocyte-committed lineages

“…27 It is difficult to comprehend the extent to which PrP C is essential for neurodevelopment in part because of some differences in biochemistry and physiology between humans and other mammals. A number of functional activities of PrP C and in particular those involved in neurotrophic activities, 19,22,23 cell adhesion, 9,23-25 cell proliferation and differentiation 19,21,[26][27][28][29][30][31] are likely to depend on sialylation of PrP C N-linked glycans. Due to an irreversible mutation in the gene encoding human Nacetylneuraminic acid hydroxylase, different kinds of sialyc acid residues are synthesized in humans compared with the rest of mammalian species: N-acetyl neuraminic acid (Neu5Ac) is produced in human, while N-glycolylneuraminic acid (Neu5Gc) is in all other mammals.…”

“…62 This result is consistent with the current study that PrP C is involved at the stage of stem cell differentiation into neural progenitor cells. Other studies reported that the positive effect of PrP C on neuronal differentiation and neurite outgrowth could be mediated via interaction of PrP C with the stress-inducible protein STI1, 18,30 laminin, 63 or the neural cell adhesion molecule NCAM. 34 In addition, PrP C could be involved in changing the balance between self-renewal and differentiation via interaction with cdk2, which is known to participate in the cell cycle G1 to S phase transition.…”

“…They include neurotrophic activities, 19,22,23 cell adhesion, 9,[23][24][25] and cell proliferation and differentiation. 19,21,[26][27][28][29][30][31] The proportion of di-vs. mono-, and unglycosylated PrP C glycoforms was found to increase in the course of neuronal differentiation, as well as upon an increase in the density of cells cultured in vitro. 32,33 The studies that used PrP C knock out and overexpresser mice revealed that PrP C expression in multipotent neural precursor cells correlates with differentiation of precursors into mature neurons during neural development and adult neurogenesis.…”

Prion potency in stem cells biology

“…This effect was mimicked in wild-type neurospheres using antibodies to impair PrP activity, showing that PrP is important for NSC maintenance. 55 As observed in other studies, PrP activity can be modulated by a secretable form of a co-chaperone protein, stress inducible protein 1 (STI1). STI1 specifically binds to PrP and leads to a significant number of biological effects such as neuritogenesis and neuroprotection 56,57 through α7 nicotinic acetylcholine receptor activity, 58 and astrocyte development, 54 and also alters in vivo processes such as short-term memory formation and longterm memory consolidation.…”

“…50 Notably, a recent study from our group highlighted the function of PrP in the biology of NSC. 55 We showed that NSC significant differences in PrP-knockdown phenotypes observed in zebrafish and PrP-null mice may be due to the activation of gene compensatory mechanisms in the embryonic stem (ES) cells selected to derive the mouse knockouts strains. 11 Hence, an examination of the immediate changes in gene expression profile upon PrP-knockout in mammalian ES cells and embryos might be helpful to clarify this issue.…”