Reparative effect of mesenchymal stromal cells on endothelial cells after hypoxic and inflammatory injury

Jesus M. Sierra-Parraga,Rutger Ploeg,Bjarne K. Møller,Carla C. Baan,Henri Leuvenink,Marco Eijken,Martin J. Hoogduijn,Ana Merino,Bente Jespersen

doi:10.1186/s13287-020-01869-3

Abstract

BackgroundThe renal endothelium is a prime target for ischemia-reperfusion injury (IRI) during donation and transplantation procedures. Mesenchymal stromal cells (MSC) have been shown to ameliorate kidney function after IRI. However, whether this involves repair of the endothelium is not clear. Therefore, our objective is to study potential regenerative effects of MSC on injured endothelial cells and to identify the molecular mechanisms involved.MethodsHuman umbilical vein endothelial cells (HUVEC) were submitted to hypoxia and reoxygenation and TNF-α treatment. To determine whether physical interaction or soluble factors released by MSC were responsible for the potential regenerative effects of MSC on endothelial cells, dose-response experiments were performed in co-culture and transwell conditions and with secretome-deficient MSC.ResultsMSC showed increased migration and adhesion to injured HUVEC, mediated by CD29 and CD44 on the MSC membrane. MSC decreased membrane injury marker expression, oxidative stress levels, and monolayer permeability of injured HUVEC, which was observed only when allowing both physical and paracrine interaction between MSC and HUVEC. Furthermore, viable MSC in direct contact with injured HUVEC improved wound healing capacity by 45% and completely restored their angiogenic capacity. In addition, MSC exhibited an increased ability to migrate through an injured HUVEC monolayer compared to non-injured HUVEC in vitro.ConclusionsThese results show that MSC have regenerative effects on injured HUVEC via a mechanism which requires both physical and paracrine interaction. The identification of specific effector molecules involved in MSC-HUVEC interaction will allow targeted modification of MSC to apply and enhance the therapeutic effects of MSC in IRI.

Highlights

The renal endothelium is a prime target for ischemia-reperfusion injury (IRI) during donation and transplantation procedures
After 6 h, 39% of Mesenchymal stromal cells (MSC) migrated towards non-injured Human umbilical vein endothelial cells (HUVEC)
Exposure of HUVEC to hypoxia and reoxygenation led to the migration of 61% of the added MSC towards HUVEC (Fig. 1d)

Summary

Introduction

The renal endothelium is a prime target for ischemia-reperfusion injury (IRI) during donation and transplantation procedures. MSC are adult multipotent cells present in most tissues in the adult human body [9, 10] These cells are known for their regenerative and anti-inflammatory properties, which have been explored in a number of small animal [11,12,13] and large animal [14,15,16] injury models. Several phase I trials have shown that MSC therapy is safe and suggest that their immunoregulatory and regenerative properties might lead to an improved kidney transplantation outcome [18,19,20,21] In most of these studies, the MSC were given via intravenous (IV) infusion which led to entrapment of MSC in the pulmonary capillaries that prevented MSC delivery to the injured kidney [22]. Data suggest that MSC may possess renal regenerating effects after administration to the kidney [25], it is unknown whether this involves endothelial repair, and if so which mechanisms are involved

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