Endogenous Cell Stimulation and Exogenous Cell Transplantation to Promote Repair in the Central Nervous System

Regenerative strategies involving endogenous stem cell stimulation or exogenous stem cell transplantation provide promise in devastating diseases and traumatic injuries of the central nervous system, such as stroke. With only tissue plasminogen activator approved for the treatment of stroke, there is significant opportunity to design alternative strategies; however, the blood-brain barrier poses a significant barrier, limiting access to the brain using traditional intravenous and oral delivery strategies.

In order to overcome the BBB, we have designed a local delivery strategy that circumvents this barrier. By delivering therapeutic biomolecules directly to the brain tissue, we propose to stimulate the endogenous stem cells that line the lateral ventricles. We build on previous research where the sequential, co-delivery of epidermal growth factor (EGF) and erythropoietin (EPO) successfully promoted tissue repair in an endothelin-1 mouse model of stroke [1]. Here, we test endogenous stem cell stimulation in a larger, endothelin-1 rat model of stroke with the local delivery of two molecules that promote neural precursor activation: cyclosporine A and EPO. The two molecules are separately encapsulated in PLGA microspheres and dispersed in a hyaluronan/methylcellulose (HAMC) hydrogel, which is then injected directly on the cortex. We examine tissue and locomotor functional repair over 6 weeks.

Simultaneously, in a separate set of studies, we investigate cell transplantation strategies. We build on previous research where mouse neural precursor cells injected into the lesion site promoted tissue and functional repair [2]. Cells injected in the HAMC hydrogel showed greater cell survival and functional repair relative to controls. Here, we test transplantation of human-induced pluripotent stem cells differentiated to cortically-specified neuroectodermal precursor cells. We investigate the role of in vitroneuronal maturation on transplanted cell survival, tissue and functional repair in a rat endothelin-1 model of stroke.

In these studies of endogenous stem cell stimulation and exogenous stem cell transplantation to the central nervous system, we tackle key challenges of the field including cell survival and cell integration. Our strategies at the intersection of engineering and biology will be highlighted.

Acknowledgments: We are grateful to: the Canadian Institute for Health Research (CIHR) and Medicine by Design for funding (to MSS, CM and AN), the Natural Sciences and Engineering Research Council for a graduate student scholarship (to SP), and to the Ontario Graduate Scholarship and CIHR TPRM for graduate student scholarships (to AT)

References:

[1] Wang, Y.; Cooke, M.J.; Sachewsky, N; Morshead, C.M.; Shoichet, M.S. 2013 "Bioengineered sequential growth factor delivery stimulates brain tissue regeneration after stroke", J Control Rel, 172: 1-11

[2] Ballios, B.G.; Cooke, M.J.; Clarke, L.; Cole, B.; Morshead, C.M.; van der Kooy, D.; Shoichet, M.S. 2015 "A hyaluronan based injectable hydrogel improves the survival and integration of stem cell progeny following transplantation" Stem Cell Reports, 4: 1031-45