Transplanted glial restricted precursor cells improve neurobehavioral and neuropathological outcomes in a mouse model of neonatal white matter injury despite limited cell survival

Abstract

Objective Neonatal White Matter Injury (NWMI) is the leading cause of cerebral palsy and other neurocognitive deficits in prematurely-born children, and no restorative therapies exist. Our objective was to determine the fate and effect of glial restricted precursor cell (GRP) transplantation in an ischemic mouse model of NWMI. Methods Neonatal CD-1 mice underwent unilateral carotid artery ligation on postnatal-day 5 (P5). At P22, intracallosal injections of either eGFP+ GRPs or saline were performed in control and ligated mice. Neurobehavioral and postmortem studies were performed at four and eight weeks post-transplantation. Results GRP survival was comparable at one month but significantly lower at two months post-transplantation in NWMI mice compared to unligated controls. Surviving cells showed better migration capability in controls; however, the differentiation capacity of transplanted cells was similar in control and NWMI. Saline-treated NWMI mice showed significantly altered response in startle amplitude and pre-pulse inhibition paradigms compared to unligated controls, while these behavioral tests were completely normal in GRP-transplanted animals. Similarly, there was significant increase in hemispheric myelin basic protein density, along with significant decrease in pathologic axonal staining in cell-treated NWMI mice compared to saline-treated NWMI animals. Interpretation The Reduced long-term survival and migration of transplanted GRPs in an ischemia-induced NWMI model suggests that neonatal ischemia leads to long-lasting detrimental effects on oligodendroglia even months after the initial insult. Despite limited GRP-survival, behavioral and neuropathological outcomes were improved after GRP-transplantation. Our results suggest that exogenous GRPs improve myelination through trophic effects in addition to differentiation into mature oligodendrocytes.

Comparative analysis of the beneficial effects of treadmill training and electroacupuncture in a rat model of neonatal hypoxia-ischemia

“…These findings suggest that perinatal HI alters development through a delay in maturation of affected cell types, including neurons and oligodendroglia (2,21,22). Behavioral deficits are associated with white matter injury, as well as the expression of MBP in white matter (23,28,29).…”

Glial-Restricted Precursors Protect Neonatal Brain Slices from Hypoxic-Ischemic Cell Death Without Direct Tissue Contact

“…Additionally, our group recently showed that GRPs are able to improve structural as well as functional outcomes in a mouse model of ischemic neonatal white matter injury [18]. Despite these encouraging results, the mechanisms by which transplanted GRPs ameliorate outcome remain poorly understood FIG.…”

“…Notably, none of the described studies was conducted in neonates, whose brain displays its own characteristic environment that is barely comparable to that of the adult. Thus, although we used native GRPs in our previous [18] as well as in the current study, future investigations comparing different preparations of transplantable cells in the context of a newborn, developing brain will be highly relevant in the transition process from pre-clinical to clinical studies. Importantly, even the slightest possibility of pain or a similar adversity has to be excluded before the step from bench to bedside can safely be made.…”

“…These cells have been proposed as a potential therapeutic approach for a series of neurological disorders, including neonatal brain injury, which is characterized by disturbances in both white and gray matter of the central nervous system [13][14][15][16][17]. We have previously shown that GRPs improve neurobehavioral and neuropathological outcomes after neonatal ischemia-induced white matter injury in mice [18]. Interestingly, an overwhelming fraction of the transplanted GRPs could not be detected after 2 months; however, animals showed improved outcomes, suggesting that GRPs exert a beneficial effect without long-term integration and differentiation in the host.…”

Mesenchymal cells of umbilical cord and umbilical cord blood as a source of human oligodendrocyte progenitors

“…A body of evidence gained from the studies on animal models supports that the goal seems to be achievable, although a great deal of investigation is to be done and efficient sources of stem cells for OPC generation are needed. Oligodendrocyte progenitor engraftments into hypomyelinated shiverer mice [Cristofanilli et al, 2011;Wang et al, 2013], demyelinated spinal cord [Cao et al, 2010;Keirstead et al, 2005;, brain injured by hypoxia-ischemia [Chen et al, 2015;Porambo et al, 2015] or inflamed rat retina [Arriola et al, 2010;Setzu et al, 2004] have been shown to trigger graft-derived myelination, although the remyelination in chronically demyelinated lesions present in such diseases as multiple sclerosis (MS) or after spinal cord injury (SCI) still remains a challenge [Foote and Blakemore, 2005;Nazm Bojnordi et al, 2014;Podbielska et al, 2013;Tanaka and Yoshida, 2014]. The above mentioned beneficial role of oligodendrocytes conferred due to the secreted factors modulating the locally ongoing processes is likely to contribute efficiently to designing therapeutic approaches based on OPC transplantation.…”