Intravenous multipotent adult progenitor cell therapy after traumatic brain injury: modulation of the resident microglia population

Journal of Neuroinflammation

Charles S Cox¹  Shibani Pati³  Robert W Mays²  Chelsea P Thomas⁴  Philippa Smith⁴  Jason A Hamilton²  Hasen Xue⁴  Fernando Jimenez⁴  Shinil K Shah¹  Supinder S Bedi⁴  Peter A Walker⁴ 

[1] Michael E DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices, Texas A & M University, College Station, TX, USA;Department of Regenerative Medicine, Athersys Inc, 3201 Carnegie Avenue, Cleveland, OH, 44115, USA;Department of Surgery, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 5.236, Houston, TX, 77030, USA;Pediatric Surgery, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 5.236, Houston, TX, 77030, USA

关键词: Microglia;    Blood brain barrier;    Splenocytes;    Stem cells;    Traumatic brain injury;    Multipotent adult progenitor cells;   

Others  :  1160222
DOI  :  10.1186/1742-2094-9-228

 received in 2012-06-10, accepted in 2012-09-06,  发布年份 2012

【 摘 要 】

Introduction

We have demonstrated previously that the intravenous delivery of multipotent adult progenitor cells (MAPC) after traumatic brain injury affords neuroprotection via interaction with splenocytes, leading to an increase in systemic anti-inflammatory cytokines. We hypothesize that the observed modulation of the systemic inflammatory milieu is related to T regulatory cells and a subsequent increase in the locoregional neuroprotective M2 macrophage population.

Methods

C57B6 mice were injected with intravenous MAPC 2 and 24 hours after controlled cortical impact injury. Animals were euthanized 24, 48, 72, and 120 hours after injury. In vivo, the proportion of CD4⁺/CD25⁺/FOXP3⁺ T-regulatory cells were measured in the splenocyte population and plasma. In addition, the brain CD86⁺ M1 and CD206⁺ M2 macrophage populations were quantified. A series of in vitro co-cultures were completed to investigate the need for direct MAPC:splenocyte contact as well as the effect of MAPC therapy on M1 and M2 macrophage subtype apoptosis and proliferation.

Results

Significant increases in the splenocyte and plasma T regulatory cell populations were observed with MAPC therapy at 24 and 48 hours, respectively. In addition, MAPC therapy was associated with an increase in the brain M2/M1 macrophage ratio at 24, 48 and 120 hours after cortical injury. In vitro cultures of activated microglia with supernatant derived from MAPC:splenocyte co-cultures also demonstrated an increase in the M2/M1 ratio. The observed changes were secondary to an increase in M1 macrophage apoptosis.

Conclusions

The data show that the intravenous delivery of MAPC after cortical injury results in increases in T regulatory cells in splenocytes and plasma with a concordant increase in the locoregional M2/M1 macrophage ratio. Direct contact between the MAPC and splenocytes is required to modulate activated microglia, adding further evidence to the central role of the spleen in MAPC-mediated neuroprotection.

【 授权许可】

   
2012 Walker et al.; licensee BioMed Central Ltd.

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