Defects in subventricular zone pigmented epithelium‐derived factor niche signaling in the senescence‐accelerated mouse prone‐8

Abstract

We studied potential changes in the subventricular zone (SVZ) stem cell niche of the senescence-accelerated mouse prone-8 (SAM-P8) aging model. Bromodeoxyuridine (BrdU) assays with longtime survival revealed a lower number of label-retaining stem cells in the SAM-P8 SVZ compared with the SAM-Resistant 1 (SAM-R1) control strain. We also found that in SAM-P8 niche signaling is attenuated and the stem cell pool is less responsive to the self-renewal niche factor pigmented epithelium-derived factor (PEDF). Protein analysis demonstrated stable amounts of the PEDF ligand in the SAM-P8 SVZ niche; however, SAM-P8 stem cells present a significant expression decrease of patatin-like phospholipase domain containing 2, a receptor for PEDF (PNPLA2-PEDF) receptor, but not of laminin receptor (LR), a receptor for PEDF (LR-PEDF) receptor. We observed changes in self-renewal related genes (hairy and enhancer of split 1 (Hes1), hairy and enhancer of split 1 (Hes5), Sox2] and report that although these genes are down-regulated in SAM-P8, differentiation genes (Pax6) are up-regulated and neurogenesis is increased. Finally, sheltering mammalian telomere complexes might be also involved given a down-regulation of telomeric repeat binding factor 1 (Terf1) expression was observed in SAM-P8 at young age periods. Differences between these 2 models, SAM-P8 and SAM-R1 controls, have been previously detected at more advanced ages. We now describe alterations in the PEDF signaling pathway and stem cell self-renewal at a very young age, which could be involved in the premature senescence observed in the SAM-P8 model.

PEDF-derived peptide promotes skeletal muscle regeneration through its mitogenic effect on muscle progenitor cells

“…PSP 29-mer and 20-mer are small peptides derived from the 44-mer that mimic PEDF to induce satellite cell proliferation. Recently, cumulative evidence indicates that the patatin-like phospholipase domaincontaining protein 2 (PNPLA2) receptor is essential for mediating the promitotic signaling of PEDF on human embryonic stem cell and neural stem cell (11,19). Further studies are required to determine the expression of PNPLA2 in muscle satellite cells and the involvement of PNPLA2 in mediating PEDF/PSP promitotic signaling.…”

PEDF-derived peptide promotes tendon regeneration through its mitogenic effect on tendon stem/progenitor cells

“…PSP, as full-length PEDF, has been shown to initiate signaling by binding to the cell surface receptor, patatin-like phospholipase domain-containing protein 2 (PNPLA2). PNPLA2 receptor is essential for PEDF/PSP to induce mitogenic signaling on human embryonic stem cells and neural stem cells, as well as antiapoptotic signaling on hepatocytes [13, 38, 39]. Further studies are warranted to determine the expression of PNPLA2 in TSPC and the involvement of PNPLA2 in mediating PEDF/29-mer mitogenic signaling.…”

Pigment Epithelium-Derived Factor (PEDF) is a Determinant of Stem Cell Fate: Lessons from an Ultra-Rare Disease

“…In vitro , PEDF or drugs that increase PEDF cause neurospheres to proliferate [ 29 , 77 ]. These effects were also relevant to murine models of accelerated senescence (SAM-P8) where NSCs demonstrated diminished self-renewal and increased neuronal differentiation properties in response to PEDF [ 78 ]. Interestingly, senescence itself has been shown to diminish levels of endogenous PEDF, although endogenous levels of PEDF were not established in SAM-P8 mice [ 79 ].…”