Transplanting Rac1-silenced bone marrow mesenchymal stem cells promote neurological function recovery in TBI mice

Dongdong Huang, Felix Siaw-Debrah, Hua Wang, Sheng Ye, Kankai Wang, Ke Wu, Ying Zhang, Hao Wang, Chaojie Yao, Jiayu Chen, Lin Yan, Chun Li Zhang, Qichuan Zhuge, Jianjing Yang

Research output: Contribution to journalArticlepeer-review

Abstract

Bone marrow mesenchymal stem cells (BMMSCs)-based therapy has emerged as a promising novel therapy for Traumatic Brain Injury (TBI). However, the therapeutic quantity of viable implanted BMMSCs necessary to initiate efficacy is still undetermined. Increased oxidative stress following TBI, which leads to the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling pathway, has been implicated in accounting for the diminished graft survival and therapeutic effect. To prove this assertion, we silenced the expression of NADPH subunits (p22-phox, p47-phox, and p67-phox) and small GTPase Rac1 in BMMSCs using shRNA. Our results showed that silencing these proteins significantly reduced oxidative stress and cell death/apoptosis, and promoted implanted BMMSCs proliferation after TBI. The most significant result was however seen with Rac1 silencing, which demonstrated decreased expression of apoptotic proteins, enhanced in vitro survival ratio, reduction in TBI lesional volume and significant improvement in neurological function post shRac1-BMMSCs transplantation. Additionally, two RNA-seq hub genes (VEGFA and MMP-2) were identified to play critical roles in shRac1-mediated cell survival. In summary, we propose that knockdown of Rac1 gene could significantly boost cell survival and promote the recovery of neurological functions after BMMSCs transplantation in TBI mice.

Original languageEnglish (US)
Pages (from-to)2822-2850
Number of pages29
JournalAging
Volume13
Issue number2
DOIs
StatePublished - Jan 2021

Keywords

  • BMMSCs
  • NADPH
  • Rac1
  • TBI
  • neurological function recovery

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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