Topical application of adipose tissue-derived mesenchymal stem cells (ADMSCs) reduced cerebral edema in experimental traumatic brain injury (TBI)\u2014a preliminary study

Hui Ma,Cindy S W Tong,Lian Xu Cui,Kin K Y Lo,George K C Wong,Ping Kuen Lam,Wai Sang Poon

doi:10.1186/s41016-020-00219-9

Abstract

BackgroundOur previous studies showed that topical application of mesenchymal stem cells (MSCs) improved functional recovery in rat traumatic brain injury (TBI) model, and hypoxic precondition further enhanced the therapeutic effects of MSCs. There was no previous study on the attenuation of cerebral edema by MSCs.We investigated whether topical application of normoxic and hypoxic MSCs could reduce cerebral edema in an experimental TBI model.MethodsTwo million normoxic (N = 24) and hypoxic (N = 24) MSCs were applied topically to exposed the cerebral cortex in a controlled cortical impact (CCI) model. The MSCs were fixed in position with fibrin glue. No treatment was given to control animals (TBI only: n = 24). After surgery, four animals in each group were sacrificed daily (day 1 to day 6) for edema evaluation. Normal animals without TBI were used as reference (n = 4). The expressions of GFAP, AQP4, and MMP9 were also investigated by immunofluorescence staining and RT-PCR at day 3.ResultsThe edema peaked within 3 days after TBI. Compared with the control, hypoxic MSCs reduced brain water content significantly (p < 0.05). Both hypoxic and normoxic MSCs downregulated the expression of MMP9 and normalized AQP4 distribution to astrocyte end feet.ConclusionOur preliminary study showed that topical application of hypoxic MSCs suppressed both vasogenic and cytotoxic edema formation.

Highlights

Our previous studies showed that topical application of mesenchymal stem cells (MSCs) improved functional recovery in rat traumatic brain injury (TBI) model, and hypoxic precondition further enhanced the therapeutic effects of MSCs
Hypoxic MSCs reduced brain water content The brain water content increased remarkably within 3 days after TBI (Fig. 2) (Table 2). It reduced significantly in the hypoxic MSC group (p < 0.05 vs control), whereas no significant change was found in the normoxic group (Fig. 3)
Hypoxic MSCs normalized the AQP4 distribution Double fluorescent staining of GFAP and AQP4 indicated that AQP4 distribution was normalized to the end feet of astrocytes after either normoxic or hypoxic MSC treatment, whereas a positive fluorescent signal was observed around the cell body of astrocyte in the control group (Fig. 4)

Summary

Introduction

Our previous studies showed that topical application of mesenchymal stem cells (MSCs) improved functional recovery in rat traumatic brain injury (TBI) model, and hypoxic precondition further enhanced the therapeutic effects of MSCs. Conventional managements to reduce cerebral edema include (i) general measures: optimal head and neck position, adequate oxygenation, maintenance of normotension, management of fever and hyperglycemia, and nutritional support; (ii) specific interventions: controlled hyperventilation, osmotherapy (mannitol, hypertonic saline), corticosteroid administration, and pharmacological coma (barbiturates); and (iii) surgical procedures: cerebrospinal fluid (CSF) drainage, decompressive craniectomy, and decompressive laparotomy [2]. These passive treatments can induce complications such as renal failure and acute respiratory distress syndrome [2]. Known as cellular or ionic edema, is defined as “cellular failure with disrupted ionic pump with anaerobic metabolism” which is caused by ischemia after TBI [5]

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Discussion

Conclusion