Shear Stress Induces Differentiation of Endothelial Lineage Cells to Protect Neonatal Brain from Hypoxic-Ischemic Injury through NRP1 and VEGFR2 Signaling.
Neonatal hypoxic-ischemic (HI) brain injuries disrupt the integrity of neurovascular structure and lead to lifelong neurological deficit. The devastating damage can be ameliorated by preserving the endothelial network, but the source for therapeutic cells is limited. We aim to evaluate the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from adipose-derived stem cells (ASCs) and the possible intracellular signals to protect HI injury using cell-based therapy in the neonatal rats. The ASCs expressed early endothelial markers after biochemical stimulation of endothelial growth medium. The ELCs with full endothelial characteristics were accomplished after a subsequential shear stress application for 24 hours. When comparing the therapeutic potential of ASCs and ELCs, the ELCs treatment significantly reduced the infarction area and preserved neurovascular architecture in HI injured brain. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) was important for ELC migration and following in vivo therapeutic outcomes. Therefore, the current study demonstrated importance of mechanical factor in stem cell differentiation and showed promising protection of brain from HI injury using ELCs treatment.
Institute of Basic Medical Sciences, National Cheng Kung University, No. 1 Daxue Road, Tainan 701, Taiwan.
Chia-Wei
CW
Huang
Institute of Clinical Medicine, National Cheng Kung University, No. 1 Daxue Road, Tainan 701, Taiwan ; Department of Pediatrics, Taipei Medical University, No. 250 Wuxing Street, Taipei 110, Taiwan.
Chao-Ching
CC
Huang
Institute of Oral Medicine, National Cheng Kung University, No. 1 Daxue Road, Tainan 701, Taiwan.
Yuh-Ling
YL
Chen
Department of Occupational Therapy, I-Shou University, No. 1 Syuecheng Road, Kaohsiung 824, Taiwan.
Shih-Chen
SC
Fan
Division of Plastic Surgery, National Cheng Kung University Hospital, No. 138 Sheng Li Road, Tainan 701, Taiwan.
Yuan-Yu
YY
Hsueh
Institute of Clinical Medicine, National Cheng Kung University, No. 1 Daxue Road, Tainan 701, Taiwan.
Chien-Jung
CJ
Ho
Institute of Basic Medical Sciences, National Cheng Kung University, No. 1 Daxue Road, Tainan 701, Taiwan ; Department of Cell Biology and Anatomy, National Cheng Kung University, No. 1 Daxue Road, Tainan 701, Taiwan ; Department of Biomedical Engineering, National Cheng Kung University, No. 1 Daxue Road, Tainan 701, Taiwan ; International Research Center for Wound Regeneration and Repair, National Cheng Kung University, No. 1 Daxue Road, Tainan 701, Taiwan.
Chia-Ching
CC
Wu
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D007238:Infarction / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D039942:Neuropilin-1 / Q000096:biosynthesis / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism; D013314:Stress, Mechanical; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics*
D039942:Neuropilin-1; C000602029:Kdr protein, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D051058:Oncogene Protein v-akt