Circulating endothelial and endothelial progenitor ...

Transactions of the Royal Society of South Africa, 2018 https://doi.org/10.1080/0035919X.2018.1459928

Circulating endothelial and endothelial progenitor cells in microvascular repairs in pancreatic hyperglycaemic-induced damage: a review Danie J. Le Roux & Venant Tchokonte-Nana

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Islet and MSK Research Group, Anatomy and Histology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Western Cape, South Africa *Author for correspondence: E-mail: [email protected]; [email protected]

The body vasculature contains an inner lining of endothelium, which consists of highly metabolic active endothelial cells (ECs). In microvascular damage resulting from the detrimental physiological effects of hyperglycaemia, ECs are unable to change their glucose transport rate. This results in the mobilisation and recruitment of endothelial progenitor cells (EPCs) to the site of injury for neovascularisation and vascular repair. This review assessed the implications of circulating endothelial and endothelial progenitor cells (CEPCs) on pancreatic microvascular repair and highlighted the impact of EPCs in neovascularisation. This insight information may open up new avenues of research on novel approaches to maintaining and regenerating microvasculature in diabetes mellitus. Keywords: CEC; CEPC; diabetes mellitus; hyperglycaemia; vascular repair

Introduction The blood and lymphatic circulatory systems are the main transport systems in which substances are suspended or dissolved and carried via a vessel from one part of the body to another. The vessels of the blood system contain an inner lining of endothelium which consists of highly metabolic active endothelial cells (ECs), which are an important component of various physiological processes (Aird, 2012). Control of vasomotor tone, transferring blood cells from blood to underlying interstitial space, regulation of nutrient substances, angiogenesis, permeability and both innate and adaptive immunity are just some functions of ECs (Aird, 2012; Cines et al., 1998). To maintain these functions, cells have membrane bound receptors that respond to various stimuli such as growth factors, low-density lipoproteins (LDLs), nitric oxide (NO), coagulant and anti-coagulant proteins. In prolonged exposure to high glucose levels (11 mmol/L) (hyperglycaemia), the ECs are unable to change their glucose transport rate, which results in intracellular hyperglycaemia, causing significant microvascular damage within organ tissue (Veiraiah, 2005). Various other factors contribute to the extent of hyperglycaemic effects on microvascular damage such as genetic susceptibility, hypertension and dyslipidemia (Giacco & Brownlee, 2010). Interestingly, hyperglycaemia selectively damages certain mature cells such as ECs, due to cells not adapting to the changing extracellular conditions. These damaged ECs are released into the circulation (Burger & Touyz, 2012) as circulating endothelial cells (CECs) (Erdbruegger et al., 2006; Woywodt et al., 2003). Two studies (Lamping, 2007; Zhang et al., 2014) suggest that any form of vascular damage causes increased recruitment of endothelial progenitor cells (EPCs) from the bone marrow towards the site of injury to release paracrine factors necessary to promote angiogenesis and vascular repair. These © 2018 Royal Society of South Africa

Published online 19 Jun 2018

endothelial progenitor cells in peripheral and umbilical blood are called circulating endothelial progenitor cells (CEPCs) (Asahara et al., 1997). The implications of these circulating endothelial and endothelial progenitor cells on pancreatic microvascular repairs are the focus of this review. The morphohistology of the endothelial cell (EC) The EC is a single squamous epithelial cell which lines blood vessels. Its thickness varies from 0.1 μm in veins and capillaries to 1 μm in the aorta and it has a central nucleus (Aird, 2007). Capillaries have three types of endothelia that are classified according to their intercellular junctions (Bennett et al., 1959). The fenestrated endothelium consists of trans-cellular pores 50–60 nm wide, each sealed by a 5–6 nm thick diaphragm (Bennett et al., 1959). This endothelium is usually associated with organs involved in filtration or secretion. The continuous endothelium is joined by tight junctions and attached to a continuous basal membrane and is mostly found in arteries, capillaries and veins of the skin, heart, muscle, lung and brain (Alberts et al., 2002). The discontinuous endothelium is found in sinusoidal vascular beds in the liver, as well as the spleen and bone marrow (Alberts et al., 2002). The endothelium is characterised by large 100–200 nm wide fenestrations with no diaphragm and the basement membrane is poorly structured (Pries & Kuebler, 2006). The shape of ECs is heavily dependent on which blood vessel they are located in (Kibria et al., 1980). In the aorta for example, the ECs are reported (Sumagin & Sarelius, 2006) to be long and narrow, with their long tails orientated in the direction of the blood flow. In the pulmonary artery the ECs are broader and shorter, almost rectangular in shape, while the ECs of veins are large and round in shape (Kibria et al., 1980). The ECs of the inferior vena cava (IVC) are narrow, long and rectangular (Kibria et al., 1980). In arterioles, the

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ECs are spindle shaped while in capillaries they are shaped irregularly (Kibria et al., 1980; Sumagin & Sarelius, 2006). As described by Elmore (2007), other morphological changes in ECs are seen during apoptosis using tinctorial staining. Activation of apoptosis causes the cell to shrink and the cytoplasm becomes dense with tightly packed organelles. Chromatin condensation occurs, also known as pyknosis, followed by plasma membrane blebbing. The nucleus becomes fragmented and chromatin is distributed around the cytoplasm in a process called karyorrhexis. The cell fragments into apoptotic bodies, which consist of tightly packed organelles with nuclear fragments. These apoptotic bodies are degraded or digested through a process called phagocytosis by macrophages. There is evidence (Dignat-George & Boulanger, 2011) of microparticles – activated or remnants of apoptotic ECs after vascular injury – inducing endothelial regeneration by activating proliferation of mature ECs. These microparticles activate angiogenesis due to deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and messenger RNA that they retained from their original ECs (Deregibus et al., 2007). In addition, during the detachment-induced programmed cell death (anoikis), ECs are released into the blood circulation as circulating endothelial cells (CECs). The circulating endothelial cell (CEC) The intima of vascular endothelium releases mature ECs into circulation after vascular damage (Burger & Touyz, 2012). These mature ECs form a very small portion of the blood (5 cells/mL) and are approximately 15–50 μm in diameter, known as circulating endothelial cells (CECs) (Erdbruegger et al., 2006; Woywodt et al., 2003). It is believed (Sabatier et al., 2009) that CECs detach from the intima of the endothelium during a process called anoikis (detachment-induced programmed cell death) because the cells are normally anchorage-dependent (Hasmim et al., 2005). Thus, CECs are expected to increase during vascular disease (Woywodt et al., 2003). There are multiple causes (Sabatier et al., 2009) leading to anoikis of CECs with mechanical damage to the endothelium or defective adhesive properties of ECs being the most probable. Proteases released by granulocytes in certain disease states or cytokines may mediate impaired adhesion properties of ECs (Boehme et al., 2002). Integrin detachment can impair ECs’ association with focal adhesion kinase and inhibits survival signals, ultimately leading to anoikis (Shechter et al., 2009). Additionally, patients that have undergone percutaneous catheter interventions display higher levels of CECs, thus proving mechanical damage can also lead to detachment (Mutin et al., 1999). Patients diagnosed with granulomatosis with polyangiitis (Wegner’s) in a cohort (Holmen et al., 2005) investigating vasculitis and kidney involvement seem to release a circulating endothelial inflammatory cell into circulation from the endothelial site of inflammation (Holmen et al., 2005). These cells may induce increased release of neutrophil-activating chemokines and NO synthase (Holmen et al., 2005). This could possibly change the way we view CECs because these apoptotic CECs have the capability of activating inflammatory signals in quiescent ECs (Shet et al., 2003). Furthermore, CEC levels can be used to determine endothelial status and endothelial function (Erdbruegger et al., 2006). For example, CEC levels are inversely correlated with flow-mediated vasodilation in patients with congestive heart failure (Chong et al., 2004) and

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positively correlated with circulating biomarkers for endothelial dysfunction such as IL-6, von Willebrand factor (vWF) and soluble E-selectin (Boos et al., 2006; Chong et al., 2004). The heterogeneity and morphology of the CEC population varies according to the health or disease state of a person (Dignat-George & Sampol, 2000). The cells may be necrotic, healthy or even apoptotic and can appear as solitary cells, conglomerates of cells or microparticles (Dignat-George & Sampol, 2000). In a healthy patient, two-thirds of CECs are apoptotic (Solovey et al., 1999) while in sickle cell anaemia two-thirds of CECs are alive and the rest apoptotic (Solovey et al., 1999). CECs in other diseases such as vasculitis (Woywodt et al., 2003) and bacterial infections such as Rickettsia (George et al., 1993) are mostly necrotic. It remains unclear which methods for quantification of CECs is best (Erdbruegger et al., 2006). Numerous antigens such as CD146, CD106, CD141, CD105, CD54, CD62e and CD31 are used for identification of cells from endothelial origin (Erdbruegger et al., 2006). For CEC identification, CD146 is commonly used. However, the antigen is also expressed on Tcells and stromal cells (Elshal et al., 2005). Thus, CD146 is usually used in combination with other biomarkers to identify CECs. In flow cytometry, D146, CD45 and CD31 are used in combination to identify CECs. Currently, the preferred method for CEC identification is immunomagnetic separation (George et al., 1992), which is also used for the identification of the circulating endothelial progenitor cells (CEPCs) which are important elements in vascular repair.

The circulating endothelial progenitor cell (CEPC) The circulating endothelial progenitor cells (CEPC) are endothelial progenitor cells (EPCs) derived from bone marrow found in peripheral and umbilical blood (Asahara et al., 1997). These CEPCs would migrate to a site of vascular injury to stimulate the development of blood vessels to improve blood flow in a process called postnatal vascularisation (Asahara et al., 1997). However, early cell surface markers used to identify the EPC are co-expressed by endothelial and hematopoietic cells (Félétou, 2011). Fortunately this problem has been resolved to some extent with recent research (Yoder, 2012), indicating that cells identified as EPCs probably represent various hematopoietic cells in various stages of differentiation. The term EPC is thus defined as a cell that can differentiate into endothelial lineage. Due to the expression of CD133, CD34 and vascular endothelial growth factor 2 (VEGF-2) on their surface, EPCs are considered as derivatives of hemangioblasts (George et al., 2011). Both the hemangioblasts and EPCs have the ability to differentiate and proliferate into mature ECs (George et al., 2011). Multipotent adult progenitor cells (MAPCs) from bone marrow also differentiate into EPCs. These cells express VEGF-2 and CD133, but not vascular endothelial cadherin or CD34 (Yoder, 2012). Similarly, monocytic cells derived from bone marrow differentiate in EPCs and form mature ECs which express the surface markers VEGF-2, CD45 and vWF when cultured (George et al., 2011). The MAPCs, monocytic cells and hemangioblasts are thus three groups of progenitors that differentiate into EPCs in vivo. Furthermore, there are two groups of in vitro EPCs. Firstly, early EPCs that are derived from monocytes and express CD11b, CD11c, CD45 and CD14 on their surface; and secondly, late EPCs that do not express CD14 or CD45, but are thought to

Danie J. Le Roux & Venant Tchokonte-Nana Circulating endothelial and endothelial progenitor cells in microvascular

be a subgroup of CD14- CD34-KDR- (kinase insert domain protein receptor) cells (Yoder, 2010). Pathogenesis of microvasculatory dysfunction in diabetes mellitus (DM) Numerous reports (Duby et al., 2004; Joussen et al., 2004; Mogensen & Christensen, 1984) on microvascular complications related to DM focus on retinopathy, neuropathy and nephropathy. The evidence of vascular damage as a result of hyperglycaemia involves blood vessels throughout the body. There seems to be paucity in the literature on pancreatic microvascular damage or dysfunction because of hyperglycaemia. In general, microvascular dysfunction is preceded by a variety of mechanisms (Madonna & De Caterina, 2011), such as the imbalance between nitric oxide (NO) and endothelins. NO levels decrease while the increase of certain endothelins (Liu et al., 1995) triggers microvascular dysfunction. Additionally, the bradykinin B2 receptor, which inhibits the action of bradykinin (Shibuya et al., 1996), and gabexate mesilate, which inhibits thrombin, trypsin, kallikrein and plasmin action (Chen et al., 1996), have been shown to improve pancreatic microcirculation during certain disease conditions, such as acute pancreatitis (AP). These peptides are possibly involved in the pathogenesis of AP microcirculatory dysfunction. Also, AP induces activation of leukocytes to attach to microvascular endothelium. This involves the increase of endothelial and leukocytic adhesion molecules such as leukocytic β2-integrin cluster of differentiation (CD) 11b and endothelial immunoglobulin intracellular adhesion molecule (ICAM-1). Excessive leukocyte activation leads to increased release of lysosomal enzymes and reactive oxygen species (ROS), ultimately causing damage to pancreatic microvasculature by peroxidation of cell membrane lipids (Kuroda et al., 1994). In type 1 diabetes (T1D), the EC layer of capillaries in the islets also becomes more susceptible to blood leukocyte adhesion. These T-cells are insulin specific and can destroy both endothelial and beta-cells (Savinov et al., 2003), leading

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to loss of islet capillaries during early stages of T1DM. This is caused by beta (β) -cell secretion of insulin or insulin peptides which, together with major histocompatibility complex (MHC), form an antigen presented by the ECs. The T-cells then target cells expressing the antigen (Savinov et al., 2003). Moreover, vascular ECs exposed to cytokine treatment in vitro present antigens to which helper T-cells attach (Greening et al., 2003). The general mechanism of hyperglycaemia-induced vascular damage respects five underlying mechanisms: (1) increased flux through the polyol pathway, (2) increased flux through the hexosamine pathway, (3) increased protein kinase C (PKC) activation, (4) increased intracellular advanced glycation end product (AGE) formation, (5) increased receptor expression for AGEs and their activating ligands (Giacco & Brownlee, 2010). It is therefore thought that the overproduction of ROS by mitochondria (Brownlee, 2005) activate all five of these mechanisms. The ROS superoxide is overproduced by the mitochondrial electron-transport chain, induced by hyperglycaemia (Du et al., 2000). This is due to hyperglycaemia increasing the mitochondrial membrane voltage past the threshold necessary to cause superoxide formation, thus leading to increased production of ROS (Korshunov et al., 1997). Superoxide then inhibits the key glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), which develops intercellular hyperglycaemia in the cell and catalyses the 6th step of glycolysis (Figure 1). Glycolytic intermediate upstream of GAPDH increases, which ultimately causes the increase flux of the five above mentioned mechanisms (Yao & Brownlee, 2010). The increase in steady levels of ROS is the very definition of oxidative stress, which in turn plays a pivotal role in the development of microvascular damage (Son, 2007). NO is an important mediator for the vascular endothelium in the regulation of blood flow because of its antiplatelet, permeability-decreasing, anti-oxidant, anti-inflammatory, antiproliferative and vasodilatory properties (Harrison, 1997).

Figure 1. Scheme of the direct action of hyperglycaemia leading to apoptosis and cellular damage.

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However, oxidative stress diminishes the production of NO by ECs or inhibits its biological activity. Therefore, the endothelium loses its inhibition of leukocyte adhesion and rolling. Monocyte chemotactic protein-1 (MPC-1) as well as cytokineinduced expression of vascular cell adhesion molecule-1 (VCAM-1) is also increased due to decreased NO (van den Oever et al., 2010). Furthermore, cellular stress, caused by oxidative stress, produces intrinsic signals which can induce apoptosis (van den Oever et al., 2010). In normal physiological conditions, apoptosis is a regulated and controlled process of cell death, also known as programmed cell death (PCD), and is required for the health of multicellular organisms and normal development (van den Oever et al., 2010). However, in hyperglycaemic conditions, ECs can be overly sensitive to apoptosis (van den Oever et al., 2010) due to inhibitory activities of the oxidative stress on NO. The apoptotic inhibitory function of NO is reduced, leading to an

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increase in the apoptotic rate of ECs (van den Oever et al., 2010). Recruitment and mobilisation of CECs and CEPCs for vascular repair In vascular damage caused by ischaemia and hypoxia (Figure 2) there is activation of hypoxic inducible factor 1α (HIF-1α) – a dimeric protein complex that plays an important part in the body’s response to low oxygen concentration (Wels et al., 2008). HIF-1α, a sub-unit of HIF-1, then induces the synthesis of vascular endothelial growth factor (VEGF), which activates the enzyme matrix metalloproteinase-9 (MMP-9) in bone marrow stromal cells (Heissig et al., 2002; Wels et al., 2008). This enzyme degrades the extracellular matrix of the bone marrow, leading to the transformation of membrane crossing Kit ligand (mKitL) to solubility Kit ligand (sKitL) (Heissig et al., 2002). Bone marrow-derived

Figure 2. Simplified scheme of the mobilisation of CEPCs following vascular damage.

Danie J. Le Roux & Venant Tchokonte-Nana Circulating endothelial and endothelial progenitor cells in microvascular

EPCs, positive for c-kit, are activated to shift from the quiescent stromal niche into the bone marrow sinusoids (Heissig et al., 2002). The c-kit positive cells express chemokine receptor-4 (CXCR4) to which an essential trigger of EPC mobilisation binds to. The trigger, stromal derived factor (SDF 1), also known as motif chemokine 12 (CXCL12), which is expressed by ECs, is regulated by HIF-1α. Thus, CXCL12-dependent recruitment of regenerative c-kit positive EPC is mediated by injured arteries and hypoxic tissue which up-regulates HIF1α (Ceradini et al., 2004). In addition, CXC chemokine receptor-2 (CXCR2) is expressed by EPCs (Hristov et al., 2007). Cell adhesion molecules (CAMs), such as P-selectin, function more specifically on the surfaces of activated ECs and platelets, while E-selectin functions only on ECs activated by cytokines (Foubert et al., 2007). However, the expression of E-selectin is stimulated by the production of P-selectin, both playing an important role in inflammation, as they are all involved in recruitment and mobilisation of EPCs in vivo (Foubert et al., 2007). Beta-1 and 2 integrins are receptors for cell adhesion that have also been implicated with mediating homing of EPCs to the periphery as well as the migration of EPC across the ECs. Most recently, β-thromboglobulin secreted by active platelets was identified to also cause EPC recruitment and migration due to it being a precursor for CXCL12 (Hristov et al., 2007). Taken together, the increase in the recruitment and mobilisation of EPCs is implicated to the functional ability of NO (Aicher et al., 2003). NO has been known to inhibit MMP-2 expression via the induction of Activating Transcription Factor 3 (ATF3) in ECs (Chen & Wang, 2004), which is beneficial for regeneration of damaged vessels (Feng et al., 2014). A different mechanism by which EPCs promote angiogenesis and vascular repair has been suggested (Zhang et al., 2014); instead of EPCs engrafting themselves into the damaged vasculature, they release paracrine factors inducing angiogenesis (Zhang et al., 2014). In addition, Ishida and coworkers (Ishida et al., 2012) identified CCL5/CCR5 interaction as a novel molecular target for modulation of tissue repair and vascular regeneration, while a more recent study (Tchokonte-Nana et al., 2017) found that the degree of endothelial cell damage is not uniform across organs’ vascular beds across species. Thus, the implication of EPCs in clinical medicine cannot be over emphasised. Clinical importance of CEPC The importance of quantifying CEPCs has been highly stressed in clinical practice (Chong et al., 2004; Erdbruegger et al., 2006) Numerous antigens are used in combination with biomarkers (Erdbruegger et al., 2006; George et al., 1992; Xing et al., 2012) to assess the levels of CEPCs. Thus, the levels of CEPCs are valuable tools to assess clinical outcomes (Rafat et al., 2007). High levels of CEPCs have been shown to positively correlate with VEGF in patients with kidney carcinoma (Yang et al., 2012). More so, a recent study has demonstrated that the CEPC and VEGF levels may be correlated with disease activity (Dogan et al., 2014). Because of this, during islet transplantation for the treatment of type 1 diabetes, islets are coated with either ECs or EPCs against instant blood-mediated inflammatory reaction (IBMIR), which causes substantial loss of transplanted tissue and displays anti-coagulation properties (Kim et al., 2009). ECs (Johansson et al., 2005) and late EPCs (Kim et al., 2011) were found to be an inhibitory factor to IBMIR. Various other studies (Kang et al., 2012; Oh et al., 2013; Penko et al., 2015; Quaranta et al.,

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2014) reported other beneficial effects of co-transplanting islets with EPCs. EPCs re-vascularise islet grafts faster, leading to enhanced graft perfusion and recovery from hypoxia (Kang et al., 2012). In this instance, the transplanted islet morphology is also better preserved (Oh et al., 2013), while their initial glycaemic control is improved (Penko et al., 2015). Furthermore, in STZ-induced diabetic rats, normoglycaemia was reported six months after transplantation (Quaranta et al., 2014), suggesting an improvement in the survivability of the islets following co-transplantation with EPCs, therefore emphasising the impact of EPCs in neovascularisation. Conclusion From this review, it is evident that islet cell survival depends on the integrity of the EC microvasculature. Increasing numbers of CECs as a result of vascular damage trigger the recruitment of CEPCs from the bone marrow towards the site of injury to stimulate the release of paracrine factors from ECs necessary to promote angiogenesis and vascular repair. These protective properties of CECs and CEPCs are also required for neoangiogenesis of engrafted islets in islet cell replacement therapy in diabetes mellitus. The literature shows that the presence of ECs and EPCs in the microcirculatory environment is essential for vasculature repairs and neovascularisation. But this review brings to light the need to develop further research in establishing the mechanism through which EPCs promote EC activity, leading to microvascular repair. This may open up new avenues of novel approaches to maintaining and regenerating microvasculature in DM. ORCID Venant Tchokonte-Nana

http://orcid.org/0000-0003-2240-3735

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