Endothelial colony-forming cells and pro-angiogenic cells: clarifying definitions and their potential role in mitigating acute kidney injury

Abstract

Acute kidney injury (AKI) represents a significant clinical concern that is associated with high mortality rates and also represents a significant risk factor for the development of chronic kidney disease (CKD). This article will consider alterations in renal endothelial function in the setting of AKI that may underlie impairment in renal perfusion and how inefficient vascular repair may manifest post-AKI and contribute to the potential transition to CKD. We provide updated terminology for cells previously classified as 'endothelial progenitor' that may mediate vascular repair such as pro-angiogenic cells and endothelial colony-forming cells. We consider how endothelial repair may be mediated by these different cell types following vascular injury, particularly in models of AKI. We further summarize the potential ability of these different cells to mitigate the severity of AKI, improve perfusion and maintain vascular structure in pre-clinical studies.

Keywords: angiogenesis; fibrosis; inflammation; ischaemia; rarefaction.

Figure 1

Alterations in endothelial function contribute to the extension phase of acute kidney injury. On the left, a peritubular capillary is shown in close apposition to tubular epithelium in a normal kidney. B) In response to injury, endothelial swelling narrows capillary space. Increased adhesion molecule expression facilitates leukocyte attachment, contributing to erythrocyte rouleaux formation and disrupting normal blood flow. Reduction in flow contributes to reduced shear stress and inhibition of NO formation, a potential trigger for endothelial mesenchymal transition (EndoMT). Addition potential contributors toward EndoMT include a reduction in trophic support from damaged tubules or injury activated perictyes. Disruption of blood flow exacerbates tissue hypoxia and further compromises epithelial injury and a reduction in renal

Figure 2

Failed vascular recovery leads to peritubular capillary rarefaction following AKI. Concurrent with resolution of GFR and tubular repair recovery of the capillary endothelium is inefficient due to a combination of EndoMT and low endothelial proliferation. Infiltration of pro-angiogenic hematopoietic cells provide pro-angiogenic stimulation but renal endothelium is unresponsive due to the lack of HPP-ECFC activity intrinsic in kidney. Expansion of fibroblasts or myofibroblasts, which derive from either pericyte activation or EndoMT, may occlude blood vessels leading to a rarefied capillary bed.

Figure 3

Human “endothelial progenitor cells” (EPC) have been identified using monoclonal antibodies or specific ligands to detect numerous cell surface antigens. Three key antigens CD34, AC133, and KDR are the most frequently utilized as markers for human EPC. No unique antigen has been reported that can discriminate the human EPC from other cell lineages (many of the above antigens are present on blood cells).

Figure 4

Proangiogenic hematopoietic cells (PHC) do not become endothelial cells but do stimulate resident endothelial colony forming cells (ECFC) to repair the intima. Moving from the left to the right on the image, one can visualize that any denudation injury that causes loss or turnover of the resident endothelial cells results in an area of exposed subendothelial basement membrane. Circulating platelets would be readily recruited to the exposed basement membrane and would release chemokines and growth factors to recruit circulating PHC, ranging from bone marrow progenitor cells to mature circulating monocytes and neutrophils, to assist in adhering to the basement membrane. The recruited PHC secrete a host of growth factors, chemokines, and proteolytic enzymes to stimulate the proliferation and migration of resident ECFC into the site of the injury to reconstitute the endothelial barrier and promote normal homeostatic functions through the injured vessel segment. The PHC merely migrate into the tissue where they can differentiate into mature tissue resident cells, re-enter the circulation, or undergo senescence and are cleared by macrophages in the tissues.

Figure 5

Both HPP-ECFC and pro-angiogenic hematopoietic cells can mitigate acute kidney injury. Both cell types have been shown to improve renal function and renal perfusion when administered prior to the establishment of renal injury. Possible mechanisms include a direct inhibition of adhesion molecule expression proposed to maintain perfusion in the early injury phase (See Figure 1). Maintenance of vascular structure likely is based on prevention of endothelial loss for which EndoMT represents a primary mechanism. Protection is likely mediated by released factors such as pro-angiogenic factors or exosomal transfer of microRNA to protect endothelial injury. Whether administered ECFC could repopulate capillary endothelium is currently subject to debate (likely depends on mode of administration). We propose that co-operative activity of both HPP-ECFC and pro-angiogenic hematopoietic cells could potentially lead to successful engraftment in the acutely injured kidney.