Stem cells to regenerate the newborn brain

Perinatal hypoxia-ischemia (HI) is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. In this thesis we investigate whether mesenchymal stem cells (MSC) regenerate the neonatal brain after HI injury. We show that transplantation of MSC after neonatal brain injury is an effective way to repair the damaged brain. One injection of MSC enhances proliferation, differentiation and results in decreased lesion volume and improved motor function. A second injection of MSC is more powerful in decreasing lesion volume and improving motor function. The effect of MSC treatment is also represented by remodeling of the corticospinal tract; a process which is only stimulated after a second injection with MSC. In search for the underlying mechanisms, we show that the administered MSC do not survive for long in the brain of the recipient, but do stimulate endogenous repair processes. Stimulation of repair by MSC is mediated via growth factors and is dependent on the bi-directional interplay between the administered MSC and the ischemic environment in the brain. MSC respond to signals provided by the cerebral environment into which they are transplanted and adapt their growth and differentiation factor profile to the demands of the environment. We propose that communication between resident and transplanted stem cells regulates repair of the brain after injury. Finally, we show that MSC can enter the brain after nasal administration and that MSC accumulate at the site of injury. The combination of an easy to use administration route together with the extended therapeutic time window for MSC treatment and potent regeneration of lost brain tissue renders MSC treatment an excellent candidate for treatment of newborn babies with brain injury within the near future

A guide to the BRAIN initiative cell census network data ecosystem

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.Horizon 2020 (H2020)R01 NS096720Radiolog