Cardiovascular disease in renal patients—a matter of stem cells?

Danilo Fliser, Kirsten de Groot, Ferdinand Hermann Bahlmann and Hermann Haller

1 Department of Internal Medicine, Hannover Medical School, Hanover, Germany

Correspondence and offprint requests to: Danilo Fliser, MD, Division of Nephrology, Department of Internal Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. Email: fliser.danilo{at}mh-hannover.de

Keywords: cardiovascular disease; endothelial progenitor cells; haematopoietic progenitor cells; renal failure



   Stem cells in cardiovascular medicine
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 EPCs in patients with...
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Stem cells have emerged as a new exciting therapeutic option for a variety of conditions in cardiovascular medicine such as myocardial infarction, heart failure and peripheral vascular disease. The encouraging results from recent experimental and animal studies are currently being tested in several clinical trials, focusing mainly on the treatment of patients with acute myocardial infarction and/or heart failure [1–4]. For this purpose, mostly bone marrow-derived mononuclear cells (BMCs) have been obtained directly from the patient's bone marrow by aspiration and eventually expanded ex vivo before intra-coronary or even intravenous (i.v.) application. The majority of these rather small studies primarily explored the feasibility and safety of this experimental approach. In the first randomized controlled trial from the Department of Internal Medicine of the Hannover Medical School, several parameters of cardiac function were assessed in patients who received intra-coronary BMCs after acute myocardial infarction [5]. The preliminary results are positive and will certainly boost the enthusiasm of the cardiovascular community for large-scale studies. Of even greater importance than stem cell therapy of acute myocardial dysfunction could be the prevention of progression of chronic atherosclerotic vascular disease and its associated syndromes. In this respect, BMCs seem less useful than circulating progenitor cells, because the latter can be—at least theoretically—persistently stimulated in vivo by targeted pharmacological interventions.



   Endothelial progenitor cells—what are they and what can they do?
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Endothelial progenitor cells (EPCs) have come into focus in cardiovascular research recently because they are thought to be responsible for endothelial and, hence, vascular repair [6,7]. This has been investigated extensively in experimental studies using different animal models of cardiovascular injury and repair [8–10]. EPCs circulate in the vasculature, where they home and incorporate into sites of active neovascularization [11,12]. In fact, EPCs orchestrate re-endothelialization of damaged vessel walls, also by secreting a large number of important cytokines which attract and govern cells that are indispensable in the process of endothelial repair [13,14]. Data obtained in human studies are even more intriguing; in patients with coronary artery disease, the number of EPCs correlates strongly with the number of cardiovascular risk factors, and this correlation exists even in apparently healthy subjects without manifest atherosclerosis [15,16]. In the latter population, the number of EPCs also correlates significantly with the degree of endothelial dysfunction [16]. Furthermore, in clinical conditions known to be associated with increased cardiovascular risk, such as diabetes mellitus, the number and/or function of EPCs is diminished [17].

EPCs are considered to originate from CD34+ haematopoietic stem cells (HSCs), which differentiate via separate pathways into erythrocytes, thrombocytes, various lineages of leukocytes and endothelial cells. These mononuclear cells can be analysed in patient's peripheral blood by flow cytometry using different stem cell surface marker proteins such as CD34 and CD133, as well as their morphological qualities [18]. In contrast, flow cytometry of EPCs is still plagued by technical difficulties, partly because of their very small number in the peripheral circulation which hampers their identification and subdivision. Due to their adhesion on culture plates, EPCs can be isolated from the peripheral blood mononuclear cell fraction, however, and can be identified further in culture by different endothelial cell marker characteristics [6,7]. Theoretically, their number can be expanded in vitro for therapeutic use [2].



   EPCs in patients with renal disease
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Renal patients are characterized by extremely high cardiovascular morbidity and mortality, and most die of complications related to atherosclerosis, namely myocardial infarction and stroke [19]. Numerous cardiovascular risk factors are thought to play a role, but the idea that impaired vascular repair mechanisms as a result of reduced number and/or impaired function of EPCs may contribute to the problem has not been pursued so far. We could demonstrate recently that the number of EPCs in peripheral blood is indeed significantly reduced in patients with advanced renal failure as compared with age- and gender-matched healthy subjects [20]. A similar observation has been made in patients on maintenance haemodialysis [21,22]. We also found a significant correlation between CD34+ HPCs and EPCs in renal patients, a finding that points to a problem of differentiation of precursor cells to EPCs or to reduced mobilization of EPCs from the bone marrow, or both, in uraemia. The former assumption is supported further by the observation of a significant inhibitory effect of uraemic serum on the differentiation capacity of EPCs in vitro [20]. Moreover, their capability to migrate and to form tube-like (vascular) structures in vitro is also reduced. One important factor contributing to EPC deficiency in patients with advanced renal failure could be lack of erythropoietin (EPO), since plasma EPO levels were an independent predictor of EPC levels in renal patients. Taken together, in patients with renal failure, EPC differentiation is hampered and may lead to malfunction of vascular repair mechanisms. This finding is reminiscent of the well known defects of cellular function caused by uraemic intoxication [23].



   Can we modulate the number of regenerative EPCs?
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The finding that the number of functionally active EPCs in peripheral blood can be modulated by increasing their proliferation and/or release from the bone marrow could be of over-riding therapeutic importance. Experimental work and studies in humans have revealed that the number of EPCs in peripheral blood can be increased by pharmacological interventions such as administration of statins [24,25] or angiotensin II receptor blockers (our unpublished results). Moreover, the demonstration that recombinant human EPO (rhEPO) or its analogue darbepoetin is a powerful stimulatory agent for EPC proliferation and functional activity is of particular interest for the nephrological community [26–28]. A marked and persistent stimulation of EPC recruitment in vitro and in vivo was demonstrable even at subtherapeutic rhEPO doses with respect to treatment of renal anaemia [28]. In parallel with the improvement of cellular function (e.g. tube-like formation activity), rhEPO directly activates the Akt tyrosine kinase signalling pathway in EPCs [26,28]. The stimulation of this important pro-survival cellular pathway may render EPCs more resistant against an ischaemic milieu, as has been demonstrated recently for mesenchymal stem cells genetically enhanced with Akt1, i.e. the gene encoding Akt [29].

Thus, stimulation of EPCs by administration of statins and/or rhEPO or analogues could be a new promising therapeutic strategy in regenerative cardiovascular medicine in order to prevent the sequelae of atherosclerotic vascular disease. This approach may also be useful in patients with renal failure, a population at particularly high cardiovascular risk. In this respect, administration of statins and/or rhEPO might be indicated at an earlier stage of renal failure than currently recommended.



   References
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