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Cardiomyocyte proliferation stops at birth when the heart is no longer exposed to maternal blood and, likewise, to regulatory T cells (Tregs) that are expanded to promote maternal tolerance towards the fetus. Here, we report a role of Tregs in promoting cardiomyocyte proliferation. Treg-conditioned medium promotes cardiomyocyte proliferation, similar to the serum from pregnant animals. Proliferative cardiomyocytes are detected in the heart of pregnant mothers, and Treg depletion during pregnancy decreases both maternal and fetal cardiomyocyte proliferation. Treg depletion after myocardial infarction results in depressed cardiac function, massive inflammation, and scarce collagen deposition. In contrast, Treg injection reduces infarct size, preserves contractility, and increases the number of proliferating cardiomyocytes. The overexpression of six factors secreted by Tregs (Cst7, Tnfsf11, Il33, Fgl2, Matn2, and Igf2) reproduces the therapeutic effect. In conclusion, Tregs promote fetal and maternal cardiomyocyte proliferation in a paracrine manner and improve the outcome of myocardial infarction.

Neonatal jaundice or hyperbilirubinemia is the result of alterations in the bilirubin metabolism. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological dysfunction and, if untreated, eventually death by kernicterus. Severe hyperbilirubinemia results in the saturation of the bilirubin binding capacity of plasma albumin, with the consequent increase in the fraction of unconjugated bilirubin (UCB) not bound to albumin (free bilirubin, Bf) that, due to its lipophilicity, crosses the blood brain barrier accumulating in the brain and triggering the neuronal injury. In the developing central nervous system, a wide range of cellular functions are affected and the concerted disruption of their regulation results in cellular damage. Patients experiencing prolonged toxic bilirubin levels are characterized by a number of neurological deficits, such as abnormalities in motor, sensitive and cognitive functions. Despite intensive studies, several aspects of the mechanisms operating at the onset of the disease are still partially understood. To study severe neonatal hyperbilirubinemia and possible therapies, I took advantage of the Ugt1-/- mouse model previously generated in my laboratory. Homozygous mutant mice develop jaundice and accumulate bilirubin in the brain due to the lack of the Ugt1a1 enzyme. If untreated, mutant mice show neurological deficits leading to early neonatal lethality. The work performed in this Thesis explores three different aspects of bilirubin neurotoxicity: 1. The role of Bf in vivo by the administration of human serum albumin; 2. The events preceding death by a time-course analysis of mutant pups; 3. The investigation of the role of neuroinflammation by the administration of a neuroprotective and anti-inflammatory drug. The obtained results showed that increasing plasma bilirubin-binding capacity by albumin supplementation decreases bilirubin neurotoxicity. In fact, daily albumin administration avoided t

Therapies to prevent severe neonatal unconjugated hyperbilirubinemia and kernicterus are phototherapy and, in unresponsive cases, exchange transfusion, which has significant morbidity and mortality risks. Neurotoxicity is caused by the fraction of unconjugated bilirubin not bound to albumin (free bilirubin, Bf). Human serum albumin (HSA) administration was suggested to increase plasma bilirubin-binding capacity. However, its clinical use is infrequent due to difficulties to address its potential preventive and curative benefits, and to the absence of reliable markers to monitor bilirubin neurotoxicity risk. We used a genetic mouse model of unconjugated hyperbilirubinemia showing severe neurological impairment and neonatal lethality. We treated mutant pups with repeated HSA administration since birth, without phototherapy application. Daily intraperitoneal HSA administration completely rescued neurological damage and lethality, depending on dosage and administration frequency. Albumin infusion increased plasma bilirubin-binding capacity, mobilizing bilirubin from tissues to plasma. This resulted in reduced plasma Bf, forebrain and cerebellum bilirubin levels. We showed that, in our experimental model, Bf is the best marker to determine the risk of developing neurological damage. These results support the potential use of albumin administration in severe acute hyperbilirubinemia conditions to prevent or treat bilirubin neurotoxicity in situations in which exchange transfusion may be required.

Neonatal jaundice or hyperbilirubinemia is the result of alterations in the bilirubin metabolism. Prolonged and uncontrolled high levels of unconjugated bilirubin lead to bilirubin-induced neurological dysfunction and, if untreated, eventually death by kernicterus. Severe hyperbilirubinemia results in the saturation of the bilirubin binding capacity of plasma albumin, with the consequent increase in the fraction of unconjugated bilirubin (UCB) not bound to albumin (free bilirubin, Bf) that, due to its lipophilicity, crosses the blood brain barrier accumulating in the brain and triggering the neuronal injury. In the developing central nervous system, a wide range of cellular functions are affected and the concerted disruption of their regulation results in cellular damage. Patients experiencing prolonged toxic bilirubin levels are characterized by a number of neurological deficits, such as abnormalities in motor, sensitive and cognitive functions. Despite intensive studies, several aspects of the mechanisms operating at the onset of the disease are still partially understood. To study severe neonatal hyperbilirubinemia and possible therapies, I took advantage of the Ugt1-/- mouse model previously generated in my laboratory. Homozygous mutant mice develop jaundice and accumulate bilirubin in the brain due to the lack of the Ugt1a1 enzyme. If untreated, mutant mice show neurological deficits leading to early neonatal lethality. The work performed in this Thesis explores three different aspects of bilirubin neurotoxicity: 1. The role of Bf in vivo by the administration of human serum albumin; 2. The events preceding death by a time-course analysis of mutant pups; 3. The investigation of the role of neuroinflammation by the administration of a neuroprotective and anti-inflammatory drug. The obtained results showed that increasing plasma bilirubin-binding capacity by albumin supplementation decreases bilirubin neurotoxicity. In fact, daily albumin administration avoided t

Therapies to prevent severe neonatal unconjugated hyperbilirubinemia and kernicterus are phototherapy and, in unresponsive cases, exchange transfusion, which has significant morbidity and mortality risks. Neurotoxicity is caused by the fraction of unconjugated bilirubin not bound to albumin (free bilirubin, Bf). Human serum albumin (HSA) administration was suggested to increase plasma bilirubin-binding capacity. However, its clinical use is infrequent due to difficulties to address its potential preventive and curative benefits, and to the absence of reliable markers to monitor bilirubin neurotoxicity risk. We used a genetic mouse model of unconjugated hyperbilirubinemia showing severe neurological impairment and neonatal lethality. We treated mutant pups with repeated HSA administration since birth, without phototherapy application. Daily intraperitoneal HSA administration completely rescued neurological damage and lethality, depending on dosage and administration frequency. Albumin infusion increased plasma bilirubin-binding capacity, mobilizing bilirubin from tissues to plasma. This resulted in reduced plasma Bf, forebrain and cerebellum bilirubin levels. We showed that, in our experimental model, Bf is the best marker to determine the risk of developing neurological damage. These results support the potential use of albumin administration in severe acute hyperbilirubinemia conditions to prevent or treat bilirubin neurotoxicity in situations in which exchange transfusion may be required.