Multimodal imaging of hair follicle bulge-derived stem cells in a mouse model of traumatic brain injury

Timo Schomann,Juvita D Iljas,Ivo Que,Alan Chan,Clemens M.W.G Löwik,Johan H.M Frijns,Luis J Cruz,Yuedan Li,Laura Mezzanotte,Margriet A Huisman,Ernst Suidgeest

doi:10.1007/s00441-020-03173-1

Abstract

Traumatic brain injury (TBI) is a devastating event for which current therapies are limited. Stem cell transplantation may lead to recovery of function via different mechanisms, such as cell replacement through differentiation, stimulation of angiogenesis and support to the microenvironment. Adult hair follicle bulge-derived stem cells (HFBSCs) possess neuronal differentiation capacity, are easy to harvest and are relatively immune-privileged, which makes them potential candidates for autologous stem cell-based therapy. In this study, we apply in vivo multimodal, optical and magnetic resonance imaging techniques to investigate the behavior of mouse HFBSCs in a mouse model of TBI. HFBSCs expressed Luc2 and copGFP and were examined for their differentiation capacity in vitro. Subsequently, transduced HFBSCs, preloaded with ferumoxytol, were transplanted next to the TBI lesion (cortical region) in nude mice, 2 days after injury. Brains were fixed for immunohistochemistry 58 days after transplantation. Luc2- and copGFP-expressing, ferumoxytol-loaded HFBSCs showed adequate neuronal differentiation potential in vitro. Bioluminescence of the lesioned brain revealed survival of HFBSCs and magnetic resonance imaging identified their localization in the area of transplantation. Immunohistochemistry showed that transplanted cells stained for nestin and neurofilament protein (NF-Pan). Cells also expressed laminin and fibronectin but extracellular matrix masses were not detected. After 58 days, ferumoxytol could be detected in HFBSCs in brain tissue sections. These results show that HFBSCs are able to survive after brain transplantation and suggest that cells may undergo differentiation towards a neuronal cell lineage, which supports their potential use for cell-based therapy for TBI.

Highlights

In recent years, stem cell therapy has attracted huge interest as a new therapeutic method for the treatment of brain injury.Many studies using animal models and even human clinical trials have demonstrated the potential of stem cell transplantation for the treatment of neurological disorders (Hasan et al 2017; Lemmens and Steinberg 2013)
Under the regulation of the promoter for the neuronal migration protein DCX, hair follicle bulge-derived stem cells (HFBSCs) that were transduced with the pCDH-DCX-Luc2-T2A-copepod green fluorescent protein (copGFP) construct did not express copGFP during standard cell culture as marked by the absence of any fluorescent signal (Fig. 1c–c′′)
We were able to show for the first time that HFBSCs can survive and differentiate towards a neuronal cell lineage after transplantation of these cells into the mouse brain by applying in vivo multimodal imaging, i.e., bioluminescence imaging (BLI) and magnetic resonance imaging (MRI)

Summary

Introduction

Stem cell therapy has attracted huge interest as a new therapeutic method for the treatment of brain injury.Many studies using animal models and even human clinical trials have demonstrated the potential of stem cell transplantation for the treatment of neurological disorders (Hasan et al 2017; Lemmens and Steinberg 2013). Application of autologous stem cells, such as bone marrowderived mesenchymal stromal cells (BM-MSCs) and human umbilical cord blood cells, could induce neuro-restorative effects in the brain after injury (Bang et al 2016; Caplan 2017). These effects are mainly attributed to paracrine mechanisms such as the stimulatory effect of stem cells on endogenous cells to release growth and trophic factors. The advantage of BM-MSCs is that they can be harvested from the patient allowing autologous stem cell therapy The latter allows the conduction of clinical trials using BM-MSCs in patients with traumatic brain injury (TBI) (Cox 2006; Cox 2012; SanBio 2016). Their mesodermal potency poses a risk for unwanted differentiation after transplantation (Grigoriadis et al 2011)

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