Impaired function of endothelial progenitor cells in children with primary systemic vasculitis
Ying Hong1, Despina Eleftheriou2, Nigel J Klein3
1Infection, Immunity, Immunology and Physiological Medicine, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK. y.hong@ucl.ac.uk.
Insights
Endothelial progenitor cell (EPC) function is impaired in children with systemic vasculitis (SV), despite normal cell numbers. Inflammation may contribute to this dysfunction, potentially impacting vascular repair in pediatric SV.
Area of Science:
- Pediatric Rheumatology
- Vascular Biology
- Immunology
Background:
- Children with active systemic vasculitis (SV) exhibit increased circulating endothelial progenitor cells (EPCs).
- The functional capacity of these EPCs and their correlation with disease activity in pediatric SV remain under-investigated.
- This study investigates the hypothesis that EPC function is impaired in active pediatric SV.
Purpose of the Study:
- To determine the relationship between disease activity and EPC function in pediatric SV.
- To assess the impact of systemic inflammation on EPC function, specifically examining the effects of hyperthermia and TNF-α.
Main Methods:
- A cross-sectional study involving children with SV and healthy controls.
- Isolation and functional assessment of EPCs, including colony-forming unit (EPC-CFU) assays and matrigel assays for cluster formation and HUVEC network incorporation.
- In vitro studies evaluating the effects of hyperthermia and TNF-α on EPC function.
Main Results:
- EPC-CFU and EPC cluster formation were significantly reduced in children with active SV compared to controls.
- EPC incorporation into HUVEC networks was diminished in children with SV, regardless of disease activity.
- Hyperthermia impaired EPC function ex vivo, while TNF-α reduced EPC expression of adhesion molecules and network incorporation.
Conclusions:
- EPC function is significantly impaired in children with vasculitis, contrasting with previously observed normal cell numbers.
- The chronic inflammatory environment in SV may compromise EPC function, potentially disrupting the balance between endothelial injury and repair.
- Further research is needed to elucidate the precise mechanisms underlying impaired EPC function in pediatric vasculitis.
Introduction:
Previously, we demonstrated that children with active systemic vasculitis (SV) have higher circulating CD34 + CD133 + KDR+ endothelial progenitor cells (EPC); the function of these EPCs, and their relationship with disease activity in vasculitis remains largely unexplored. We hypothesized that although EPC numbers are higher, EPC function is impaired in active SV of the young. The aims of this study were therefore to: 1. investigate the relationship between disease activity and EPC function in children with SV; and 2. study the influence of systemic inflammation on EPC function by investigating the effects of hyperthermia and TNF-α on EPC function.
Methods:
We performed a cross-sectional study of unselected children with SV with different levels of disease activity attending a single center (Great Ormond Street Hospital, London) between October 2008 and December 2014. EPCs were isolated from peripheral blood of children with SV, and healthy child controls. EPC function was assessed by their potential to form colonies (EPC-CFU), and ability to form clusters and incorporate into human umbilical vein endothelial cell (HUVEC) vascular structures in matrigel. The effects of hyperthermia and TNF-α on EPC function were also studied.
Results:
Twenty children, median age 12-years (5-16.5; nine males) were studied. EPC-CFU and the number of EPC clusters formed on matrigel were significantly reduced in children with active vasculitis compared with healthy controls (p = 0.02 for EPC-CFU; p = 0.01 for EPC cluster formation). Those with active vasculitis had lower EPC-CFU and EPC cluster formation than those with inactive disease, although non-significantly so. In addition, EPC incorporation into matrigel HUVEC networks was lower in children with SV compared with healthy children, irrespective of disease activity. Ex-vivo pre-treatment of EPC with hyperthermia impaired EPC function; TNF-α down-regulated EPC expression of CD18/CD11b and resulted in decreased incorporation into HUVEC networks.
Conclusions:
Whilst our previous work showed that circulating CD34 + EPC numbers are well preserved, this study revealed that EPC function is significantly impaired in children with vasculitis. It is possible that the chronic inflammatory milieu associated with vasculitis may impair EPC function, and thus contribute to an unfavourable balance between endothelial injury and repair. The mechanism of this remains to be established, however.
