CD44 Transmembrane Receptor and Hyaluronan Regulate Adult Hippocampal Neural Stem Cell Quiescence and Differentiation

Abstract

Adult neurogenesis in the hippocampal subgranular zone (SGZ) is involved in learning and memory throughout life but declines with aging. Mice lacking the CD44 transmembrane receptor for the glycosaminoglycan hyaluronan (HA) demonstrate a number of neurological disturbances including hippocampal memory deficits, implicating CD44 in the processes underlying hippocampal memory encoding, storage, or retrieval. Here, we found that HA and CD44 play important roles in regulating adult neurogenesis, and we provide evidence that HA contributes to age-related reductions in neural stem cell (NSC) expansion and differentiation in the hippocampus. CD44-expressing NSCs isolated from the mouse SGZ are self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes. Mice lacking CD44 demonstrate increases in NSC proliferation in the SGZ. This increased proliferation is also observed in NSCs grown , suggesting that CD44 functions to regulate NSC proliferation in a cell-autonomous manner. HA is synthesized by NSCs and increases in the SGZ with aging. Treating wild type but not CD44-null NSCs with HA inhibits NSC proliferation. HA digestion in wild type NSC cultures or in the SGZ induces increased NSC proliferation, and CD44-null as well as HA-disrupted wild type NSCs demonstrate delayed neuronal differentiation. HA therefore signals through CD44 to regulate NSC quiescence and differentiation, and HA accumulation in the SGZ may contribute to reductions in neurogenesis that are linked to age-related decline in spatial memory.

Peptide‐modified, hyaluronic acid‐based hydrogels as a 3D culture platform for neural stem/progenitor cell engineering

“…Although CD44 has been reported widely as a marker for NS/PCs, 41,111,112 immunofluorescence labeling in 3D HA hydrogels indicated sporadic CD44 presence in only a few cells in all 2D and 3D conditions. Moreover, there was a trend toward less CD44 expression in 3D compared to 2D cultures.…”

“…Hydrogels were fabricated based on hyaluronic acid (HA), a nonsulfated glycosaminoglycan that is abundant in CNS tissue and particularly enriched during embryonic development and in adult NS/PC niches . HA regulates proliferation and differentiation of Sox2 + NS/PCs through the CD44 receptor . In inflammatory environments, high molecular weight HA acts as a scavenger of damaging free radical species .…”

“…39 HA regulates proliferation and differentiation of Sox2 + NS/PCs through the CD44 receptor. 40,41 In inflammatory environments, high molecular weight HA acts as a scavenger of damaging free radical species. 42 HA hydrogels can be modified to provide additional matrix-derived functionalities, such as integrinbinding and mechanical cues, in combination.…”

Comment on: PH20 is not expressed in murine CNS and oligodendrocyte precursor cells

“…This experiment demonstrates that elevated PH20 directly blocks OPC maturation, given that contaminating factors did not exist in these experimental conditions. In addition, we recently reported3 that both bovine testicular hyaluronidase and a preparation of recombinant PH20 both had nearly identical effects on hippocampal neural stem cell proliferation and differentiation both in vitro and in vivo, and that these effects were dependent on the CD44 transmembrane hyaluronan receptor. These data similarly indicate that PH20 activity and not contaminating factors are playing a role in the biological effects of adding PH20 to cells in the nervous system.…”

A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination

“…Scutellarin, another flavonoid, reduces the severity of cuprizone-induced demyelination, possibly by preventing neural stem cell apoptosis and subsequent oligodendrocyte differentiation (Wang et al, 2016). This finding is interesting in light of our recent report demonstrating that HA regulates neural stem cell proliferation and neurogenesis in the hippocampal dentate gyrus (Su et al, 2017). All together, these studies and the data presented here suggest that flavonoids have a wide range of potential therapeutic applications in the CNS, and that these activities can be enhanced through simple chemical modifications.…”