Abstract
Stem cell treatment after stroke has demonstrated substantial outcome improvement. However, monitoring of stem cell fate in vivo is still challenging and not routinely performed, yet important to quantify the role of the implanted stem cells on lesion improvement; in several studies even mortality of the graft has been reported. Resting state functional magnetic resonance imaging (rs-fMRI) is a highly sensitive imaging modality to monitor the brain-wide functional network alterations of many brain diseases in vivo. We monitor for 3 months the functional connectivity changes after intracortical stem cell engraftment in large, cortico-striatal (n = 9), and in small, striatal (n = 6) ischemic lesions in the mouse brain with non-invasive rs-fMRI on a 9.4T preclinical MRi scanner with GE-EPI sequence. Graft vitality is continuously recorded by bioluminescence imaging (BLI) roughly every 2 weeks after implantation of 300 k neural stem cells. In cortico-striatal lesions, the lesion extension induces graft vitality loss, in consequence leading to a parallel decrease of functional connectivity strength after a few weeks. In small, striatal lesions, the graft vitality is preserved for the whole observation period and the functional connectivity is stabilized at values as in the pre-stroke situation. But even here, at the end of the observation period of 3 months, the functional connectivity strength is found to decrease despite preserved graft vitality. We conclude that quantitative graft viability is a necessary but not sufficient criterion for functional neuronal network stabilization after stroke. Future studies with even longer time periods after stroke induction will need to identify additional players which have negative influence on the functional brain networks.
Highlights
Ischemic stroke is the third most common cause of death and the leading cause for disabilities worldwide [1]
Resting state fMRI was performed 1 week before, as well as 1, 2, 4, 8, and 12 weeks after stroke induction and cell implantation (2 days after stroke induction), while vitality of the transgenic graft was monitored by bioluminescence imaging (BLI) at weeks 2, 3, 4, 5, 7, 9, 10, and 12 after stroke
Two types of ischemic lesions were found on the MRI: a small lesion restricted to the striatum (n = 6), and a large lesion encompassing the striatum plus a large part of the cortex (n = 9)
Summary
Ischemic stroke is the third most common cause of death and the leading cause for disabilities worldwide [1]. Several experimental studies on rodent models of stroke have reported outcome improvements after stem cell implantations [3,4,5,6,7,8]. Most of these studies focused on the stem cell effect on lesion volume or relied on behavioral assays for the read-out of outcome improvement [7,8,9,10,11]. Other reports concentrated mainly on the structural and functional integration of the stem cell grafts in the host tissue [12, 13]
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