Neuroprotection of the hypoxic-ischemic mouse brain by human CD117+CD90+CD105+ amniotic fluid stem cells

Michelangelo Corcelli,Anna L David,Mariya Hristova,Kate Dowding,Filipa Vlahova,Pierre Gressens,Donald Peebles,Kate Hawkins,Pascale V Guillot,Henrik Hagberg,Avina Hunjan,Paolo De Coppi

doi:10.1038/s41598-018-20710-9

Abstract

Human amniotic fluid contains two morphologically-distinct sub-populations of stem cells with regenerative potential, spindle-shaped (SS-hAFSCs) and round-shaped human amniotic fluid stem cells (RS-hAFSCs). However, it is unclear whether morphological differences correlate with functionality, and this lack of knowledge limits their translational applications. Here, we show that SS-hAFSCs and RS-hAFSCs differ in their neuro-protective ability, demonstrating that a single contralateral injection of SS-hAFSCs into hypoxic-ischemic P7 mice conferred a 47% reduction in hippocampal tissue loss and 43–45% reduction in TUNEL-positive cells in the hippocampus and striatum 48 hours after the insult, decreased microglial activation and TGFβ1 levels, and prevented demyelination. On the other hand, RS-hAFSCs failed to show such neuro-protective effects. It is possible that SS-hAFSCs exert their neuroprotection via endoglin-dependent inhibition of TGFβ1 signaling in target cells. These findings identify a sub-population of CD117+CD90+CD105+ stem cells as a promising source for the neuro-protection of the developing brain.

Highlights

Human fetal stem cells present a number of advantageous characteristics over their adult counterparts, such as faster growth kinetics, longer telomeres and higher differentiation potential[1], presenting an intermediate phenotype between adult mesenchymal stem cells and embryonic stem cells[2]
Contrary to SS-human amniotic fluid stem cells (hAFSCs), RS-hAFSCs do not express the cell surface markers CD90 (Thy-1) and CD105, indicating that these surface markers can be used for purification of heterogeneous cell adherent CD117+ (C-Kit+) human amniotic fluid stem cell populations
Human amniotic fluid, which can be retrieved during caesarean section or at birth, is a valuable source of fetal stem cells that can be used without ethical concerns for allogeneic and autologous applications in regenerative

Summary

Introduction

Human fetal stem cells present a number of advantageous characteristics over their adult counterparts, such as faster growth kinetics, longer telomeres and higher differentiation potential[1], presenting an intermediate phenotype between adult mesenchymal stem cells and embryonic stem cells[2]. Comparative analysis revealing the higher proliferation rate, differentiation potential and in vitro migration ability of SS-hAFSCs7. Their in vivo regenerative potential has not been systematically compared and most pre-clinical experiments have been performed using heterogeneous populations of hAFSCs. To determine whether the morphological and phenotypical differences observed in vitro between SS-hAFSCs and RS-hAFSCs correlate with differential functionality, we compared the neuro-repair potential of the cells using the Vannucci mouse model of neonatal hypoxic ischaemic encephalopathy (HIE)[8], whereby the left common carotid artery is permanently occluded and the mice exposed to a 60 min hypoxic challenge in 8% oxygen. We are the first to demonstrate that SS-hAFSCs, which can be isolated from heterogeneous populations of hAFSCs based on their cell surface co-expression of CD105 and CD90, have potential for the protection of the developing brain

Methods

Results

Conclusion