4 - Early Postnatal Expression of TGFβ-1 & FGF-2 Correlates with Regenerative Functions of Unrestricted Somatic Stem Cell (USSC) Infusion After Premature Rabbit Brain Hemorrhage (IVH)
Monday, May 1, 2023
9:30 AM – 11:30 AM ET
Poster Number: 4 Publication Number: 4.433
Edmund F.. LaGamma, New York Medical College, Valhalla, NY, United States; Dina Finkel, New York Medical College and The Icahn School of Medicine at Mount Sinai, Rego Park, NY, United States; Yanling Liao, New York Medical College, Elmsford, NY, United States; Mitchell S. Cairo, New York Medical College, Valhalla, NY, United States; Govindaiah Vinukonda, New York Medical College, Valhalla, NY, United States
Prof Peds, Biochem & Molec Bio New York Medical College Valhalla, New York, United States
Background: Intraventricular hemorrhage (IVH) is a severe complication of preterm birth associated with white matter injury (WMI) & reduced neurogenesis resulting in cerebral palsy & cognitive delays. IVH commonly arises from the germinal matrix – a highly cellular, transient structure from which CNS precursor cells are born, proliferate & radially migrate during brain development. IVH leads to reduced progenitor cell proliferation, maturation and attendant neuronal and WMI damage. Oligodendrocyte lineage (OLG) proliferation, maturation and survival are key for myelination; yet, successful therapies for impaired functions of OLGs after IVH are not yet defined. Objective: We evaluated whether human cord blood derived, unrestricted somatic stem cells (USSCs) could alter recovery of OLG proliferation and maturation to improve myelination after IVH in a premature rabbit pup model of IVH. USSCs release growth factors, have low class 2 HLA are thus hypo-immunogenic, and migrate to areas of injury (Vinukonda & LaGamma; Sem Perinatol 46:2022). Design/Methods: USSC at 24hours after initiation of the intraperitoneal glycerol-induced IVH in premature rabbit pups were assessed in the sub-ventricular zone, corona radiata and corpus callosum by analysis of OLG lineage-specific progression (PDGFR+, OLIG2+ and NKX2.2+) and cell division (Ki67) markers correlated with developmentally regulated growth factors: i) TGFβ1, FGF2, and IGF and ii) their mitotic regulated gene expression during postnatal development. Results: The early OLG cell lineage PDGFR+ and OLIG2+ cell immunofluorescence and cell density quantitation showed significant reduction after IVH (p< 0.05 both PDGFR+, OLIG2+ at day 3); impairment was recovered after intracerebroventricular injection of USSCs (p< 0.05 both PDGFR+, OLIG2+ at day 3 & 7). Similarly, CSF protein levels of TGFβ1 were reduced by IVH at d3 & 7 and recovered after USSC (p< 0.05 for all changes); same for its mRNA at d3. FGF2 CSF protein showed a non-significant reduction but an increase in its mRNA after USSC on d3 (p < 0.05). Common cell cyclin gene pathways were essentially unaffected but the cell cycle inhibitor P27Kip1 (CDKN1B) was increased after IVH but remained at normal levels after USSC treatment in IVH pups on day 3.
Conclusion(s): Our findings demonstrated a plausible mechanism for myelination regenerative functions of USSCs by recovery of OLIG proliferation and maturation along with correlative early changes in key growth factor expression in the developing injured IVH brain. These effects offer the possibility that USSCs have translational potential as therapy in preterm neonates.
