Combination of human endothelial colony-forming cells and mesenchymal stromal cells exert neuroprotective effects in the growth-restricted newborn

Stephanie M Miller,Seen-Ling Sim,Paul B Colditz,Kirat K Chand,S T Bjorkman,Jatin Patel,Kiarash Khosrotehrani,Jane Sun,Elliot Teo,Lara Jones,Julie A Wixey

doi:10.1038/s41536-021-00185-5

Abstract

The foetal brain is particularly vulnerable to the detrimental effects of foetal growth restriction (FGR) with subsequent abnormal neurodevelopment being common. There are no current treatments to protect the FGR newborn from lifelong neurological disorders. This study examines whether pure foetal mesenchymal stromal cells (MSC) and endothelial colony-forming cells (ECFC) from the human term placenta are neuroprotective through modulating neuroinflammation and supporting the brain vasculature. We determined that one dose of combined MSC-ECFCs (cECFC; 106 ECFC 106 MSC) on the first day of life to the newborn FGR piglet improved damaged vasculature, restored the neurovascular unit, reduced brain inflammation and improved adverse neuronal and white matter changes present in the FGR newborn piglet brain. These findings could not be reproduced using MSCs alone. These results demonstrate cECFC treatment exerts beneficial effects on multiple cellular components in the FGR brain and may act as a neuroprotectant.

Highlights

Foetal growth restriction (FGR) occurs in around 3–15% of pregnancies with even greater rates in developing countries[1,2,3]
We further investigated whether the improved vascular structure and organisation in the FGR brain that occurred with combined mesenchymal stromal cells (MSCs)-Endothelial colony forming cells (ECFCs) (cECFC) treatment, resulted in maintenance of BBB integrity
This study provides evidence that postnatal intervention of placentally derived cECFC treatment affords neuroprotection in the FGR piglet

Summary

INTRODUCTION

Foetal growth restriction (FGR) occurs in around 3–15% of pregnancies with even greater rates in developing countries[1,2,3]. No treatments currently exist to protect the FGR newborn brain Both neuronal and white matter alterations are observed in both the human FGR infant and animal models of FGR11–16. Endothelial colony forming cells (ECFCs) are the vascular precursors, devoid of hematopoietic and myeloid contamination[28] They reside throughout the vasculature, have self-renewal as well as a capacity to engraft forming both de novo neo-vessels as well as chimeric vessels within ischaemic sites of the host, facilitating reperfusion and initiating tissue regeneration[29,30]. Analysis of the CD34, a marker of restore the NVU, reduce brain inflammation and improve adverse hematopoietic stem cells and vascular endothelial progenitor neuronal and white matter changes present in the FGR newborn cells[39], closely reflected the observations of Col IV labelling with piglet brain.

RESULTS

DISCUSSION

Findings

METHODS