Hyaluronan-CD44 Interaction Regulates Mouse Retinal Progenitor Cells Migration, Proliferation and Neuronal Differentiation

Background: Therapeutic applications of retinal progenitor cells (RPCs) are hindered by their limited proliferation and differentiation capacity and poor ability to migrate into damaged retinal tissue. Our study aimed to explore the effects of HA-CD44 interactions on the regulation of RPCs migration, proliferation and differentiation, and to investigate the underlying regulation mechanisms.Methods: Mouse RPCs were isolated and amplified. Western blot and flow cytometry analyses were used to investigate the expression of CD44 in RPCs. The effects of HA-CD44 interactions on the RPCs behaviors, including migration, proliferation and differentiation, were investigated by MTT assay, CCK8 assay, vertical collagen gel invasion assay, time-lapse imaging, immunocytochemistry, RT-PCR and western blot assay. Furthermore, the downstream signals of HA-CD44 interactions were investigated.Results: CD44 was expressed in RPCs, and HA-CD44 interaction markedly improved RPCs adhesion and migration. The stimulation of miR-21 expression by HA-CD44 interaction was PKC/Nanog-dependent in RPCs. Treatment of RPCs with PKC- or Nanog-specific ASODN or miR-21 antagomir effectively blocked HA-mediated RPCs adhesion and migration. Moreover, ROK/Gab-1 associated PI3K/AKT signaling activation was required in the HA-CD44 interaction mediated RPCs proliferation and neuronal differentiation.Conclusions: Our findings demonstrated new roles for HA-CD44 interaction in regulating both migration, proliferation and neuronal differentiation of RPCs. HA-CD44 signaling could comprise a novel approach to control RPC fates, which may be instructive for the application of RPCs for future therapeutic application.