PMID- 36788590 OWN - NLM STAT- MEDLINE DCOM- 20230216 LR - 20230217 IS - 1757-6512 (Electronic) IS - 1757-6512 (Linking) VI - 14 IP - 1 DP - 2023 Feb 14 TI - Endothelial colony forming cell administration promotes neurovascular unit development in growth restricted and appropriately grown fetal lambs. PG - 29 LID - 10.1186/s13287-023-03249-z [doi] LID - 29 AB - BACKGROUND: Fetal growth restriction (FGR) is associated with deficits in the developing brain, including neurovascular unit (NVU) dysfunction. Endothelial colony forming cells (ECFC) can mediate improved vascular stability, and have demonstrated potential to enhance vascular development and protection. This investigation examined whether ECFCs from human umbilical cord blood (UCB) enhanced NVU development in FGR and appropriate for gestational age (AGA) fetal sheep. METHODS: Twin-bearing ewes had surgery performed at 88-90 days' gestation, inducing FGR in one fetus. At 113 days, ECFCs (1 x 10(7) cells) cultured from human UCB were administered intravenously to fetal sheep in utero. At 127 days, ewes and their fetuses were euthanised, fetal brains collected, and NVU components analysed by immunohistochemistry. RESULTS: Twenty-four fetal lambs, arranged in four groups: AGA (n = 7), FGR (n = 5), AGA + ECFC (n = 6), and FGR + ECFC (n = 6), were included in analyses. FGR resulted in lower body weight than AGA (P = 0.002) with higher brain/body weight ratio (P = 0.003). ECFC treatment was associated with increased vascular density throughout the brain in both AGA + ECFC and FGR + ECFC groups, as well as increased vascular-astrocyte coverage and VEGF expression in the cortex (P = 0.003, P = 0.0006, respectively) and in the subcortical white matter (P = 0.01, P = 0.0002, respectively) when compared with the untreated groups. CONCLUSIONS: ECFC administration enhanced development of NVU components in both the AGA and FGR fetal brain. Further investigation is required to assess how to optimise the enhanced angiogenic capabilities of ECFCs to provide a therapeutic strategy to protect the developing NVU against vulnerabilities associated with FGR. CI - (c) 2023. The Author(s). FAU - Bell, Alexander AU - Bell A AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. AD - Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. FAU - Watt, Ashalyn P AU - Watt AP AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. FAU - Dudink, Ingrid AU - Dudink I AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. AD - Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. FAU - Pham, Yen AU - Pham Y AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. FAU - Sutherland, Amy E AU - Sutherland AE AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. FAU - Allison, Beth J AU - Allison BJ AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. AD - Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. FAU - McDonald, Courtney A AU - McDonald CA AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. AD - Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. FAU - Castillo-Melendez, Margie AU - Castillo-Melendez M AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. FAU - Jenkin, Graham AU - Jenkin G AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. AD - Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. FAU - Malhotra, Atul AU - Malhotra A AUID- ORCID: 0000-0001-9664-4182 AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. atul.malhotra@monash.edu. AD - Department of Paediatrics, Monash University, 246 Clayton Road, Clayton, Melbourne, VIC, 3168, Australia. atul.malhotra@monash.edu. AD - Monash Newborn, Monash Children's Hospital, Melbourne, Australia. atul.malhotra@monash.edu. FAU - Miller, Suzanne L AU - Miller SL AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. AD - Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. FAU - Yawno, Tamara AU - Yawno T AD - The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. AD - Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia. AD - Department of Paediatrics, Monash University, 246 Clayton Road, Clayton, Melbourne, VIC, 3168, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230214 PL - England TA - Stem Cell Res Ther JT - Stem cell research & therapy JID - 101527581 SB - IM MH - Animals MH - Sheep MH - Female MH - Humans MH - Animals, Newborn MH - *Brain MH - Fetus MH - *Brain Injuries/metabolism MH - Fetal Growth Retardation/metabolism MH - Fetal Blood/metabolism MH - Body Weight PMC - PMC9930266 OTO - NOTNLM OT - Blood brain barrier OT - Brain injury OT - Cord blood OT - ECFC OT - Endothelial progenitor cells OT - FGR OT - Repair OT - Stem cells COIS- The authors do not have any disclosures or conflicts of interest to declare. EDAT- 2023/02/16 06:00 MHDA- 2023/02/17 06:00 PMCR- 2023/02/14 CRDT- 2023/02/15 00:28 PHST- 2022/08/16 00:00 [received] PHST- 2023/02/01 00:00 [accepted] PHST- 2023/02/15 00:28 [entrez] PHST- 2023/02/16 06:00 [pubmed] PHST- 2023/02/17 06:00 [medline] PHST- 2023/02/14 00:00 [pmc-release] AID - 10.1186/s13287-023-03249-z [pii] AID - 3249 [pii] AID - 10.1186/s13287-023-03249-z [doi] PST - epublish SO - Stem Cell Res Ther. 2023 Feb 14;14(1):29. doi: 10.1186/s13287-023-03249-z.