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Original Article
| doi: 10.1111/j.1365-2796.2008.02011.x
Diabetes mellitus impairs CD133+ progenitor cell function after myocardial infarction S. Vo¨o¨1, M. Dunaeva1, J. Eggermann2, N. Stadler1 & J. Waltenberger1 From the 1Department of Cardiology, Maastricht University Medical Center (MUMC) and Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands; and 2Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany
Abstract. Vo¨o¨ S, Dunaeva M, Eggermann J, Stadler N, Waltenberger J [Maastricht University Medical Center (MUMC) and Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands; and Ulm University Medical Center, Ulm, Germany]. Diabetes mellitus impairs CD133+ progenitor cell function after myocardial infarction. J Intern Med 2009; 265: 238–249. Background. Circulating progenitor cells (PC) can positively influence the healing of ischaemic myocardium. Cardiovascular risk factors including diabetes mellitus (DM) may have a negative influence on both number and recruitment of PC. Recent evidence suggests that less differentiated CD133+PC contribute to myocardial healing and are promising candidates for therapy. Therefore, we investigated whether DM affects CD133+PC. Methods. CD133+PC were analyzed in patients following acute myocardial infarction and successful reperfusion [acute myocardial infarction (AMI, n = 45) with ⁄ without non-insulin-requiring type 2 DM (T2DM)]. Stable coronary artery disease patients (CAD, n = 45) served as stable controls. Number and phenotype of CD133+PC were assessed by flow cytometry. CD133+PC chemotaxis was assessed
Introduction A proper number and function of circulating progenitor cells (PC) positively correlates with recovery of ischaemic myocardium [1]. Thus, PC mobilization from bone marrow into the circulation and recruit-
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towards vascular endothelial growth factor, an angiogenic stimulus upregulated in AMI. The expression of anti-oxidant enzymes in CD133+PC was detected by reverse-transcriptase PCR. Results. In non-DM patients, the number of CD133+PC increased on day 3 following AMI (P = 0.0001). In contrast, no changes were observed in AMI patients with T2DM. Regarding the function of CD133+PC, an enhanced chemotactic response was observed following AMI in both non-DM (P = 0.0001) and T2DM (P = 0.007). However, the AMI-related functional activation was significantly weaker in diabetic patients (P = 0.001). Moreover, the expression of catalase was lower in CD133+PC from T2DM. Conclusions. Our results show that T2DM not only limits the abundance of CD133+PC following AMI, but also limits their activation. This might be explained by a lower resistance of CD133+PC to oxidative stress. Our data provide a possible explanation for the delayed postischaemic vascular healing and myocardial recovery in DM. Keywords: acute myocardial infarction, CD133, coronary heart disease, diabetes mellitus, progenitor cells.
ment into target tissues are important steps involved in myocardial healing. However, PC-mediated healing seems impaired under the influence of different cardiovascular risk factors such as diabetes mellitus (DM) [2, 3]. Diabetes mellitus is a major cause of vascular pathology. Type 2 DM (T2DM) is associated
S. Vo¨o¨ et al.
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Effect of diabetes mellitus on CD133+ progenitor cell function
with increased incidence and poor prognosis of coronary artery disease (CAD) [2, 3]. This can partly be explained by a negative impact of T2DM on vascular growth, i.e. as a result of an inhibitory effect on PC [2, 3]. Previous work has shown that cardiovascular risk factors – including DM – impair the availability and function of various types of PC [2, 3]. However, it is not clear yet whether CD133+PC, a subpopulation of circulating PC, are functionally affected by DM. Circulating PCs are usually described based on their positivity for CD34 marker [1–4] although its expression is not trustfully limited to PC but is expressed on mature circulating endothelial cells as well [5]. CD133 is one of the earliest markers expressed on stem cells ⁄ PC and its expression is rapidly lost during differentiation. Therefore, CD133+ cells, which mostly co-express CD34 on its surface, might be described as PC with only very little lineage commitment, containing a subgroup of particularly immature CD133+ CD34)PC. Circulating CD133+PC contribute to postischaemic healing by promoting local angiogenesis [4]. CD133+PC exert a high chemotactic response towards angiogenic stimuli that are expressed and released in ischaemic tissues [6, 7]. We have previously shown that CD133+PC become activated early after acute myocardial infarction (AMI) and show a significantly enhanced chemotactic response towards vascular endothelial growth factor (VEGF-A) [7], which represents a functionally important angiogenic growth factor upregulated in ischaemic myocardium [8–10]. Further, CD133+PC incorporate into ischaemic areas more efficiently than CD133) cells (CD133)CD34+) [4]. The border zone of ischaemic myocardium is characterized by elevated levels of oxidative stress [11]. However, PC [12], in particular the CD133+PC subpopulation [13], seem resistant to oxidative stress as they are equipped with an efficient anti-oxidative battery reflected by high expression of the anti-oxidant enzymes catalase, glutathione peroxidase (GPX) and superoxide dismutase (SOD). Once incorporated into postischaemic areas, CD133+PC are involved in healing by promoting local angiogenesis [4, 14, 15].
The CD133+PC population can be subdivided according to the surface expression pattern of VEGF receptors (VEGFR): VEGFR1+PC are likely to be early committed progenitors [16] that preferably differentiate into the haematopoietic ⁄ myeloid lineage [17], whereas VEGFR2+PC represent more immature cells capable of differentiating into several different lineages including the endothelial lineage [18]. Both subpopulations are important for vascular growth. VEGFR1+PC participate in the initiation and stabilization of newly formed vessels, whereas VEGFR2+PC promote endothelialization [16]. Considering the potential role of CD133+PC in the recovery of postischaemic myocardium following AMI, we tested the hypothesis whether CD133+PC supply (number) and ⁄ or function (VEGF-A-induced chemotaxis) are affected by T2DM. Our novel findings provide insight into DM-related PC dysfunction.
Patients and methods The present study conforms to the principles outlined in the Declaration of Helsinki. The study protocol was approved by the Ethical Committees of the Maastricht University Medical Center (The Netherlands) and Ulm University Medical Center (Germany).
Study population The present study is a prospective pilot study including subjects with stable CAD and with CAD complicated by AMI. We discontinuously recruited 45 patients hospitalized for AMI, whereby screening and inclusion was limited by the capacity of the labourintense functional cellular analysis. The diagnosis of AMI was established following guidelines [19]; only patients with medium-large infarctions were included, presenting CKmax levels greater than fivefold the upper normal limit (
