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Synergistic targets between ASC‐differentiated endothelial and neural lineage cells to prevent hypoxic‐ischemic brain injury
Author(s) -
Huang ChiaWei,
Chang YaJu,
Chien Shu,
Wu ChiaChing
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1300.8
Subject(s) - angiogenesis , biology , microbiology and biotechnology , vascular endothelial growth factor , neurogenesis , fibroblast growth factor , cancer research , immunology , receptor , vegf receptors , biochemistry
Neonatal hypoxic‐ischemic (HI) brain injury causes disruption of neurovascular integrity and leads to life‐long functional deficit in human development. These devastating consequences can be prevented by protecting the architecture of the neurovascular unit. Our lab has demonstrated the possibility to differentiate the adipose‐derived stem cells (ASCs) into endothelial lineage cells (ELCs) or neuronal lineage cells (NLCs) via microenvironmental induction and studied the therapeutic effect of the cells by transplanting ASCs, ELCs, NLCs, or combination of ELCs and NLCs (E+N) into HI brain injured neonatal rats. The combined E+N treatment showed a significantly greater decrease of infarction and apoptotic areas, and better preservation of the neurovascular structure. The E+N combinations increased the cell migration under in vitro hypoxia microenvironment. Moreover, the transplanted ELCs and NLCs were able to engraft into host tissue and promote endogenous angiogenesis and neurogenesis. We performed the RNAseq to fish out the potential targets for the differentiated ELCs and NLCs. The ELCs, induced by endothelial growth factors and laminar shear stress, migrated and contributed to the vascular structure by activating the Akt signaling through vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin 1 (NRP1). NLCs showed better ability in preserving the neural structure. The synergistic benefits in E+N combination were revealed via the cell‐cell interactions for NRP1 signaling in ELCs and C‐X‐C chemokine receptor 4 (CXCR4) and fibroblast growth factor receptor 1 (FGFR1) signaling in NLCs. Blockage of target signals in either ELCs or NLCs diminished the synergistic interaction in cell migration, homing, and protection of neurovasculature in the HI injured brain. The results in current study pointed out the potential molecular targets for the synergistic effect between ELCs and NLCs to improve the therapeutic outcome for preserving brain integrity and function after HI injury. Support or Funding Information This study was supported in part by grants from the Ministry of Science and Technology (NSC102‐2320‐B‐006‐009‐MY3) and National Health Research Institute (NHRI‐EX101‐10115EC) in Taiwan.