Mobilization of monocytic myeloid-derived suppressor cells is regulated by PTH1R activation in bone marrow stromal cells

Myeloid-derived suppressor cells(MDSCs)are bone marrow(BM)-derived immunosuppressive cells in the tumor microenvironment,but the mechanism of MDSC mobilization from the BM remains unclear.We investigated how BM stromal cell activation by PTH1R contributes to MDSC mobilization.PTH1R activation by parathyroid hormone(PTH)or PTH-related peptide(PTHrP),a tumor-derived counterpart,mobilized monocytic(M-)MDSCs from murine BM without increasing immunosuppressive activity.In vitro cell-binding assays demonstrated thatα4β1 integrin and vascular cell adhesion molecule(VCAM)-1,expressed on M-MDSCs and osteoblasts,respectively,are key to M-MDSC binding to osteoblasts.Upon PTH1R activation,osteoblasts express VEGF-A and IL6,leading to Src family kinase phosphorylation in M-MDSCs.Src inhibitors suppressed PTHrP-induced MDSC mobilization,and Src activation in M-MDSCs upregulated two proteases,ADAM-17 and MMP7,leading to VCAM1 shedding and subsequent disruption of M-MDSC tethering to osteoblasts.Collectively,our data provide the molecular mechanism of M-MDSC mobilization in the bones of tumor hosts.

Effects of Gastrodiae rhizoma on proliferation and differentiation of human embryonic neural stem cells

Objective:To investigate the effects of Gastrodiae rhizoma,a dried root of Gastrodia elata Blume,on proliferation and differentiation of human NSCs derived from embryonic stem cells.Methods:A 70%ethanol extract of Gastrodiae rhizoma(EEGR) was estimated with4-hydroxybenzyl alcohol as a representative constituent by HPLC.Results:MTT assay showed that the treatment with EEGR increased the viability of NSCs in growth media.Compared to contro1,EEGR increased the number of dendrites and denritic spines extended from a differentiated NSC.Whereas EEGR decreased the mRNA expression of Nestin,it increased that of Tuj1 and MAP2 in NSCs grown in differentiation media.Immunocytochemical analysis using confocal microscopy also revealed the increased expression of MAP2 in dendrites of EEGR-treated NSCs.Furthermore,EEGR decreased mRNA expression of Sox2 in NSCs grown even in growth media.Conclusions:In conclusion,our study demonstrates for the first time that EEGR induced proliferation and neuronal differentiation of NSCs,suggesting its potential benefits on NSC-based therapies and neuroregeneration in various neurodegenerative diseases and brain Injuries.