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

Abstract

Prion protein, PrP C , is a glycoprotein that is expressed on the cell surface beginning with the early stages of embryonic stem cell differentiation. Previously, we showed that ectopic expression of PrP C in human embryonic stem cells (hESCs) triggered differentiation toward endodermal, mesodermal, and ectodermal lineages, whereas silencing of PrP C suppressed differentiation toward ectodermal but not endodermal or mesodermal lineages. Considering that PrP C might be involved in controlling the balance between cells of different lineages, the current study was designed to test whether PrP C controls differentiation of hESCs into cells of neuron-, oligodendrocyte-, and astrocyte-committed lineages. PrP C was silenced in hESCs cultured under three sets of conditions that were previously shown to induce hESCs differentiation into predominantly neuron-, oligodendrocyte-, and astrocyte-committed lineages. We found that silencing of PrP C suppressed differentiation toward all three lineages. Similar results were observed in all three protocols, arguing that the effect of PrP C was independent of differentiation conditions employed. Moreover, switching PrP C expression during a differentiation time course revealed that silencing PrP C expression during the very initial stage that corresponds to embryonic bodies has a more significant impact than silencing at later stages of differentiation. The current work illustrates that PrP C controls differentiation of hESCs toward neuron-, oligodendrocyte-, and astrocytecommitted lineages and is likely involved at the stage of uncommitted neural progenitor cells rather than lineagecommitted neural progenitors.

Increased expression of prion protein gene is accompanied by demethylation of CpG sites in a mouse embryonal carcinoma cell line, P19C6

“…The unmethylated status at positions CpGs 9 to 46 remained unchanged. The normal cellular isoform of the prion protein, PrP C , is produced beginning in the early stages of embryonic stem cell differentiation, suggesting its participation in cell pluripotency and neurogenesis [13, 15, 17, 19]. Our observations might support the active involvement of CpG demethylations in up-regulating expression of Prnp during neuronal differentiation.…”

Sporadic Creutzfeldt–Jakob disease with glial PrPRes nuclear and perinuclear immunoreactivity

“…PrP C is normally expressed in neurons, astrocytes, and oligodendrocytes during development and adulthood . Functions of PrP C during development include modulation of the differentiation of human stem cells into neurons, astrocytes, and oligodendrocytes . Therefore, the PrP deposits here observed in glial cells are probably produced in the same cells.…”

Physiological Functions of the Cellular Prion Protein

“…For example, knocking down PrP C expression in cultured human embryonic stem cells delayed spontaneous differentiation into the three germ layers (Lee and Baskakov, 2013). In a similar manner, PrP C expression has been shown to promote guided differentiation of cultured human embryonic stem cells and neural precursors into neurons, astrocytes and oligodendrocytes (Steele et al, 2006; Lee and Baskakov, 2014). Furthermore, a role in regulating cell adhesion suggests that PrP C expression in cancer may affect the tendency to metastasise.…”