This project will provide new knowledge regarding the best regimen, timing, dose, and route of administration of human mesenchymal stem cells (H-MSC) for regenerating the brain damage in infants born preterm; born before 37 of a typical 40 weeks of gestation. Over 15 million babies are born preterm every year it is a leading cause of death and permanent disability, often due to brain damage. The H-MSC that we will comprehensively screen are FDA-approved and in the process of being produced in a GMP grade, making them suitable for future clinical trials in human preterm born infants. These H-MSC will be evaluated in a large number of rodent models mimicking the key insults and brain damage observed in human preterm infants who will develop later motor, cognitive, and behavioral deficits. We will also apply theseH-MSC in two sheep models of injury relevant to brain damage associated with preterm birth. These large animal trials are a key step before initiating clinical trials in this high risk human population. Additional Workpackages will address the mechanisms underlying the regenerative effects of these H-MSC. This project addresses the call text by value adding to current knowledge of stem cell types and applying it to a large patient group with an unmet clinical need – infants with encephalopathy of the preterm born infant. Steps on the innovation chain targeted – preclinical research, proof of concept and to a lesser degree characterization of regenerative mechanisms.