Transforming Growth Factor Beta-1 (TGFβ1) and Fibroblast Growth Factor (FGF) Correlate with Regenerative Functions of Unrestricted Somatic Stem Cell (USSC) Infusion in Premature Brain Hemorrhage

This submission has open access
Submission ID :
ESPR133
Submission Type
Submission Topic
Abstract: :

Background:  The germinal matrix (GM) is a site of proliferating neuronal & glial precursor cells & the origin of intraventricular hemorrhage (IVH) - a common complication of extreme prematurity leading to white matter injury & cerebral palsy. We previously showed that USSC administration resulted in recovery of white matter injury & improved locomotor function in a premature rabbit model of GMH-IVH (Vinukonda et al, Stem Cell Trans Med, 8:1157, 2019). Intrinsic signals from the GM & extrinsic signals from meninges, blood vessels and cerebrospinal fluid regulate cell proliferation & differentiation during normal brain development (Lehtinen, et al, 2011; Johansson, et al, 2010). We hypothesize that intracerebroventricular (ICV) USSC administration elicits regenerative potential by modulating expression of TGFβ1, FGF, and IGF1-2, enhancing progenitor cell proliferation & differentiation after IVH.

Objective: To test whether USSC administration alters the endogenous expression of growth factors: TGFβ1, FGF and IGF1-2 in IVH. Furthermore, to determine whether a change in growth factor expression after USSC infusion correlates with specific progenitor cell proliferation & differentiation, as well as recovery after white matter injury caused by IVH.

Design/Methods: A single dose of ICV USSCs (2x106) was injected in premature rabbits 1d after IP glycerol-induced IVH; naïve & non-treated IVH animals served as comparison groups. USSC effects were established from dissected ventricular ependyma, coronal slices and cerebrospinal fluid at postnatal days 3, 7 & 14.

Results: USSC survival and migration in vivo was confirmed using live animal bioluminescence imaging followed by immunostaining. We quantified total proliferating cells using Ki67-DAPI in the GM zone (GM- ventricular zone [VZ] & sub-VZ) of the lateral ventricles at 3d & observed decreased cell density in IVH (p<0.05), whereas with USSC infusion there was a trend towards recovery showing increased total proliferation. After USSC infusion, early oligodendrocyte precursor (PDGFR-Ki67 in SVZ) proliferation showed increased cell density (p<0.05) on day 3.  Late oligodendrocyte precursor (Ki67-Olig2 in the corpus callosum & corona) showed increased cell density (p<0.05) on day 3 & 7.  Known growth factors that regulate proliferation and maturation of progenitor cells were assessed (mRNA in SVZ dissected tissue & protein in CSF): TGFβ1, FGF & IGF1-2. mRNA expression was 37% lower for TGFβ1 & 47% for FGF in 3d IVH pups, whereas increased levels of mRNA for both occurred after USSC infusion (p<0.05). TGFβ1 protein levels in the CSF at 3d decreased in IVH pups (p<0.05) & increased after USSC administration (p<0.05). IGF1-2 levels were comparable between the groups at all timepoints.

Conclusion(s): USSCs removed the blockade to oligodendrocyte precursor cell division & favorably modulated TGFβ1 & FGF toward normal expression correlating with regenerative improvement after IVH.

The Regional Neonatal ICU Maria Fareri Children’s Hospital at Westchester Medical Center-NYMC Valhalla, NY, White Plains, NY, US
Children's Hospital of New Jersey, Beth Israel Medical Center
Brown University
New York Medical College
New York Medical College & Westchester Medical Center
New York Medical College Valhalla, NY
The Regional Neonatal Center at Maria Fareri Children’s Hospital of Westchester Medical Center
New York Medical College & Westchester Medical Center
New York Medical College
The Regional Neonatal ICU Maria Fareri Children’s Hospital at Westchester Medical Center-New York Medical College Valhalla, NY

Similar Abstracts by Type

Submission ID
Submission Title
Submission Topic
Submission Type
Corresponding Author
ESPR157
Clinical Research
Original science
Aditya Chhikara
ESPR302
Epidemiology
Original science
Natasha Jouk
ESPR74
Clinical Research
Original science
Alexandra Mazo