Ambient particulate matter exposure and cardiovascular diseases: a focus on progenitor and stem cells

Abstract Air pollution is a major challenge to public health. Ambient fine particulate matter (PM) is the key component for air pollution, and associated with significant mortality. The majority of the mortality following PM exposure is related to cardiovascular diseases. However, the mechanisms for the adverse effects of PM exposure on cardiovascular system remain largely unknown and under active investigation. Endothelial dysfunction or injury is considered one of the major factors that contribute to the development of cardiovascular diseases such as atherosclerosis and coronary heart disease. Endothelial progenitor cells (EPCs) play a critical role in maintaining the structural and functional integrity of vasculature. Particulate matter exposure significantly suppressed the number and function of EPCs in animals and humans. However, the mechanisms for the detrimental effects of PM on EPCs remain to be fully defined. One of the important mechanisms might be related to increased level of reactive oxygen species (ROS) and inflammation. Bone marrow (BM) is a major source of EPCs. Thus, the number and function of EPCs could be intimately associated with the population and functional status of stem cells (SCs) in the BM. Bone marrow stem cells and other SCs have the potential for cardiovascular regeneration and repair. The present review is focused on summarizing the detrimental effects of PM exposure on EPCs and SCs, and potential mechanisms including ROS formation as well as clinical implications.


Introduction
Air pollution is a major challenge to public health. Ambient particulate matter (PM) is the key component for air pollution. A recent Global Burden of Disease Study showed that PM exposure is responsible for 3.2 million deaths per year and 76 million years of healthy life lost [1]. Particulate matter exposure could be especially a major health problem in the developing countries as the fine PM levels in some developing countries are reported to be 10 times higher than that in the developed countries [2]. The majority of mortality following fine PM exposure has been related to cardiovascular diseases [1].
Particulate matter is a mixture of various particles including metals, crustal material and bio-aerosols [3,4]. The particles with a median aerodynamic diameter of <2.5 lm (PM 2.5 ) and <10 lm (PM 10 ) are of serious global health concerns because of their close association (especially PM 2.5 ) with the detrimental effects of air pollution on our health [5,6]. The PM 2.5 exposure has been reported to produce a variety of deleterious effects on cardiovascular system including (but not limited to) vascular dysfunction, reduced heart rate variability and enhanced risk for thrombosis [3,7]. Long-term exposure to PM 2.5 has been demonstrated to accelerate the process of atherosclerosis and vascular inflammation in apolipoprotein E À/À mice with high-fat diet [8], and increase blood pressure in human and animal models [9], while short-term exposure to PM 2.5 could also induce hypertension [10].
Endothelial dysfunction or injury is considered one of the major factors that contribute to the development of atherosclerosis and coronary heart disease [11,12]. Endothelial progenitor cells (EPCs) play a critical role in vascular re-endothelialization, angiogenesis and prevention of neointima formation after vascular injury [13][14][15][16]. The number and function of stem cells (SCs) and EPCs are significantly decreased in the animals exposed to PM 2.5-10 . However, the mechanism(s) for PM 2.5-10 exposure-induced impairment of EPCs is not fully understood. Current data strongly support the concept that the effect of PM-exposure on EPCs might be related to increased level of reactive oxygen species (ROS) and inflammation [17][18][19][20]. Accumulating pre-clinical and clinical data suggest that bone marrow stem cells (BMSCs) and other SCs could significantly contribute to cardiovascular regeneration and repair after damage like myocardial infarction and myocarditis. Exposure to ambient PM related to air pollution is a constant lifelong hazard for all of us. It is therefore important to summarize the adverse consequence of PM exposure on human participants. The present review is focused on the impact of PM exposure on cardiovascular system with special efforts on progenitor cells and SCs as well as related mechanisms especially ROS formation.

PM and cardiovascular diseases
It has been demonstrated that PM 2.5 exposure could induce various cardiovascular diseases including atherosclerosis, hypertension, stroke and Type 2 diabetes mellitus (DM) [21]. American Heart Association and the Environmental Protection Agency have officially acknowledged the detrimental effects of PM 2.5 on cardiovascular system and related morbidity outcome [2]. The Harvard Six Cities study showed that the cardiopulmonary mortality was increased up to 37% in the population exposed to high levels of ambient PM 2.5 over a period of 14-16 years [22]. The analysis from a population of 50 million living in the major U.S. cities (The National Morbidity, Mortality and Air Pollution Study) indicated that an increase of 10 lg/m 3 in PM 10 was related to an increase in 0.68% in cardiopulmonary mortality [23][24][25]. Every 10 lg/m 3 increase in PM 2.5 exposure was also associated with an increase in 4.5% in coronary artery disease (CAD) [26]. Conversely, it was estimated that each 10 lg/m 3 decrease in PM 2.5 was associated with an increase in 0.61 years in mean life expectancy in the United States [27]. In addition, there was a close relationship between NO 2 and PM 2.5 and the risk of acute myocardial infarction and hospitalization in the U.S [28,29]. Similarly, the Air Pollution and Health European Approach study analysed a population of 43 million in 29 large European cities, and showed that PM 10 was closely related to cardiovascular diseases [30].
Particulate matter pollution was also correlated with a significant increase in blood pressure. It has been reported that there was a 2.8 mmHg increase in systolic blood pressure and 2.7 mmHg increase in diastolic blood pressure in patients in Boston over 5 days for every 10.5 lg/m 3 increase in PM 2.5 levels [31]. Similarly, studies have shown that increased PM 2.5 levels were associated with mean increases in systolic blood pressure of 3.2 mmHg in Detroit, Michigan, USA [32]. In addition, it was observed that a significant rise in diastolic blood pressure (6 mmHg) in 23 normotensive patients after a 2-hr exposure to PM 2.5 and O 3 compared with the patients without exposure [33]. These observations support the conclusion that there is indeed a close association between increased blood pressure and PM 2.5 exposure in human participants [34].
Air pollution has been shown to increase the risk for obesity, hypertension, chronic pulmonary disease and cardiovascular disease in the elderly [35,36]. Long-term exposure to PM 2.5 could induce insulin resistance and mitochondrial alteration in adipose tissue [37], thus further causing or exaggerating DM [38,39]. These studies provide additional evidence that PM exposure is directly associated with cardiovascular diseases, and also closely related with conditions like DM directly associated with increased cardiovascular morbidity and mortality.

Progenitor cells and cardiovascular diseases
Endothelial dysfunction or injury is considered one of the major factors that contribute to the development of cardiovascular diseases like atherosclerosis [11], coronary heart disease [12], congestive heart failure [40-42] and periphery artery disease [43]. Bone marrowderived EPCs play a critical role in vascular re-endothelialization, angiogenesis and prevention of neointima formation after vascular injury [13,15,44]. There is an obvious inverse relation between the level of circulating EPCs and the risk of cardiovascular events in the patients with angiographically documented CAD [45]. Similarly, impaired function of EPCs such as deficiency in migratory response and poor angiogenic capability has a negative correlation with the severity of CAD [46]. The important role of EPCs in maintaining the structural and functional integrity of the blood vessels has been wellestablished and extensively discussed in many excellent reviews [47,48]. Thus, the level of circulating EPCs has been an important and independent predictor for cardiovascular outcome in CAD patients [45], and it is crucial to preserve the number and function of EPCs at a healthy level for the normal functionality of vasculature in patients with cardiovascular diseases. A variety of factors are critically involved in the regulation of the in vivo dynamics of EPC number and function, including (but not limited to) cytokines and growth factors like granulocytestimulating colony stimulating factor and VEGF [40-42], nitric oxide, pharmacological agents like statins [49] and environmental factors like air pollution [19,50]. Some disease states like hyperlipidaemia, DM, inflammation, oxidative stress, ischaemia and chronic heart failure are also important for the dynamic changes of EPCs in vivo [19,[51][52][53][54].
It is important to point out that the identification and characterization of EPCs have been very challenging and complex, and even controversial as excellently summarized in a few recent review articles [55][56][57]. There are currently no unified criteria to define EPCs as yet. Therefore, the terminology 'EPC' was adopted from the original papers without modification to preserve the originality. The obvious limitation or confusion was that 'EPCs' from different studies might  not be the same cell populations with different with cell markers in the literature. There are also multiple sources for circulating EPCs, including BM and non-BM origins such as liver and spleen [58,59]. The number and function of circulating EPCs could be delicately determined by the combined outcome of EPC mobilization, differentiation, proliferation and apoptosis at sites of different sources. Accumulating evidence from pre-clinical and clinical studies suggests that cell-based therapy with progenitor cells (such as EPCs, CD34 + cells, c-kit+ cells and adipose tissue progenitor cells, APCs) and SCs (including BMSCs) remains an attractive option for tissue regeneration and repair after significant damages like myocardial infarction and myocarditis or stroke [60][61][62]. To achieve the optimal outcome for cell-based therapy, the quality of the cells needs to be preserved both in the donors and in the recipients before and after the in vivo delivery. It is well known that only a small fraction of cells could survive after in vivo delivery (both locally and systematically) [63,64]. However, very little is known on how the quality (including the number and function as well as differentiation potential) of the progenitor cells and SCs could be affected by the potential factors in vivo.

PM and progenitor cells
Epidemiological and experimental studies have shown that there is an obvious relationship between exposure to airborne pollutants and poor cardiovascular health [50]. Although very limited data are available on the mechanisms for air pollution-related cardiovascular diseases, induction of endothelial dysfunction by PM 2.5 (not able to be filtered by the respiratory tract) is believed to be one of the mechanisms for the adverse effects of air pollution on cardiovascular system in a population-based study with children and adolescents [65].
It is well known that EPCs play a critical role in vascular repair, angiogenesis and maintaining normal endothelial function [13][14][15][16]. Particulate matter exposure has been reported to significantly decrease the number and function of EPCs, and thus increase the risk of cardiovascular diseases and adverse cardiovascular events. In 2010, O'Toole et al. recruited 16 healthy college students from Provo, UT, in the United States to participate in their study [18]. The city of Provo is located in a valley and the temperature inversion in the valley could lead to a temporary increase in the concentration of PM 2.5 in the atmosphere. In this study, the investigators demonstrated that episodic exposure to PM 2.5 induced reversible vascular injury, decreased circulating EPC (CD34 + /CD31 + /CD45 + /CD133 + ) levels, enhanced platelet activation, and increased plasma level of nonalbumin protein in vivo. In the same year, Liberda et al. reported that inhalation of nickel nanoparticles could result in a decrease in tube formation and chemotaxis function of EPCs (CD34 + /VEGF-R2 + / CD11b À ) in vitro as well as a reduction in EPC number in murine BM in vivo [66]. A study performed in China in 2013 also showed that PM 2.5 exposure decreased the number of EPCs (CD34 + /KDR + , CD34 + / KDR + /CD45 À or CD34 + /KDR + /CD133 + ) in circulation [67]. This Chinese study was conducted in two large adjacent communities in Jinchang and Zhangye with comparable ambient concentrations of PM 2.5 . Jinchang was identified as a heavily Nickel-polluted area because of its proximity to the second largest Nickel refinery in the world. Zhangye, 250 miles northwest and upwind from Jinchang, was selected to serve as a control community. A total of 60 healthy nonsmoking adult women residents were recruited in the study. It was observed that the circulating EPCs were significantly lower in the participants from Jinchang than those from Zhangye. Diesel exhaust particles were reported to reduce the number and function of EPCs with impaired stromal cell-derived factor (SDF)-1-induced migratory capacity and neoangiogenesis both in vivo and in vitro in a murine model. Consistent with above observation, we recently reported that PM treatment significantly decreased murine-circulating EPC population, promoted apoptosis of murine EPCs (CD34 + /CD133 + ) in association with increased ROS production and serum TNF-a and IL-1b levels in vivo (Fig. 1) [19].
However, some studies demonstrated that circulating EPCs could be increased after PM 2.5-10 exposure. Brook et al. recruited 32 healthy non-smoking adults (18-50 years old) in Dexter, a town in Michigan, United States, an area with coarse PM 2.5-10 exposures [68]. Dexter is 410 km from major freeways and 460 km west of the Detroit metropolitan area. The study showed that increased number of EPCs (CD34 + /CD133 + /CD3 À /CD79b À /CD56 À ) in vivo persisted for at least 20 hrs following brief inhalation of coarse PM 2.5-10 . The mechanism was believed to be related to a systemic reaction to an acute 'endothelial injury' and/or a circulating EPCs response to sympathetic nervous system activation. Haberzettl et al. delineated that exposure to PM 2.5 could increase murine EPC (Sca-1 + /Flk-1 + ) levels in the BM by preventing their mobilization to the peripheral blood via inhibition of signalling events triggered by VEGF-receptor stimulation based on in vivo and ex vivo experiment [17]. This might also explain the decreased circulating EPCs as a result of the decreased mobilization of BM EPCs into the circulation. PM 2.5 exposure might also have significant impact on APCs as well. Adipose tissue progenitor cells (Lin À /CD34 + /CD29 + /Sca-1 + / CD24 + ) in brown adipose tissue are closely correlated with the normal functionality of brown adipose tissue and reduction in obesity [69]. It has been shown that high level exposure to PM 2.5 in murine early life is associated with decreased number of murine APCs and increased risk factor for the development of insulin resistance, adiposity and inflammation in association with ROS generation by NADPH oxidase in vivo [70]. The effect of PM exposure on different progenitor cells and their function in both human and animals was summarized in Tables 1 and 2.

PM and stem cells
Cell-based therapy with progenitor cells and SCs appears to be a promising option for the regeneration and/or repair of damaged tissues in cardiovascular system [71][72][73][74]. Many types of SCs have been studies as the potential sources for cell-based therapy including embryonic SCs (ESCs) [75,76], neural SCs [77], cardiac SCs [78][79][80][81], BM-derived haematopoietic SCs (HSCs) [82], BM-derived c-kit + /Lin À cells [83,84], mesenchymal SCs (MSCs) [72,85,86], adiposederived SCs [87] and inducible pluripotent stem cells from somatic cells [88]. Progenitor/SCs in circulating blood and in the vascular wall could serve as the endogenous pool of SCs to restore the structural and functional integrity of the vasculature through rapid repair of the endothelial cells and/or formation of new vessels after injuries [89]. The progenitor/SCs residing in vascular intima, media and adventitia may participate in vascular repair and the formation of neointimal lesions in severely damaged vessels [90]. Recently, a new type of SCs was identified in the murine arterial media, named multipotent vascular SCs, which could differentiate into neural cells and MSC-like cells and subsequently differentiate into SMCs [91]. In addition, abundant progenitor/SCs expressing Sca-1 have been identified in the adventitia, which may contribute to endothelial regeneration and smooth muscle accumulation in the neointimal lesions [92].  The therapeutic efficacy of cell therapy for cardiovascular diseases is associated with a variety of factors including cell types, myocardial ischemia, cardiac dysfunction or their combination [93]. The outcome of cell therapy with stem cells could be also related to the engraftment and survival of the cells transplanted into the target area such as an infarcted myocardial area. It is known that one of the major challenges for cell therapy with BMSCs is the low viability of the implanted cells with the loss of cells occurring mainly in the first few days after in vivo delivery [94]. However, the mechanisms for the poor in vivo survival of the cells are complex, and have yet to be defined. It is believed that an acute inflammatory reaction with formation of various inflammatory factors including inducible nitric oxide synthase in the delivery site is a critical factor for the cell death in the first 24-72 hr period [94][95][96].
Unfortunately, there is very little data available in the area of PM 2.5 and SCs. We recently found that PM exposure significantly decreased murine BMSCs population in vivo, defined as lineage negative/Sca-1 positive (LS) and lineage negative/CD133 positive (Lin À /CD133 + ) cells, in association with increased ROS formation, decreased level of Akt phosphorylation and inhibition of in vivo proliferation of murine BMSCs without induction of apoptosis [20]. We further demonstrated that PM-induced ROS production was the major mechanism for decreased in vivo proliferation and population of murine BMSCs. Treating mice with antioxidant N-acetylcysteine (NAC) or using a triple transgenic mouse line with overexpression of antioxidant enzyme network (AON) composed of superoxide dismutase (SOD)1, SOD3 and glutathione peroxidase-1 with decreased in vivo ROS production significantly decreased murine BMSCs intracellular ROS level, partially reversed the suppression of p-Akt expression, effectively reversed the inhibition of BMSCs proliferation rate and restored the BMSCs population in the mice with PM exposure in vivo (Fig. 1). There are a variety of sources for PM exposure [97]. Recent studies showed that the median concentration of PM 2.5 in the smoking area (both indoor and outdoor) was significantly higher than in the control area [98][99][100]. Thus, environmental tobacco smokeassociated PM could be an important independent health hazard in addition to the well-known toxic and carcinogenic compounds contained in cigarette smoking (CS). It has been reported that CS could significantly impair the number and function of various SCs including ESCs, spermatogonial SCs (SSCs) and Clara cell (SCs of the bronchiolar epithelium). Cigarette smoking could produce cytotoxic action on human ESCs (hESCs) and mouse ESCs (mESCs), induce oxidative stress, apoptosis and telomere shortening in ESCs in vitro, inhibit cell adhesion and growth in vitro, and compromise embryo development in vivo [101][102][103]. In addition, CS might also induce mutation of SSCs gene and alterations in hESCs gene expression (especially those characteristic for mesoderm and ectoderm development) in vivo [104]. Increased expression of Notch, Wnt or transforming growth factor-b genes by smoking resulted in retention of the cells in pluripotent state in vivo [105]. In addition, acute exposure of mESCs to CS or cadmium could cause immediate cell death, and decrease their pluripotency, while chronic exposure could lead to DNA damage and telomere shortening in vivo [106,107]. Coal dust exposure resulted in the disappearance of proliferating cell nuclear antigen in rat Clara cell in vivo [108]. Although CS could recruit SCs into murine lung in vivo [109,110], negative impact including interfering murine and human MSCs homing by targeting microvascular endothelial cells and differentiation into endometrial cells and blood vessel ex vivo were reported [111,112]. The detrimental effects of PM exposure and CS on SCs were summarized in Tables 1 and 2. However, it is important to differentiate the effect of PM exposure from that of other toxic and carcinogenic compounds in CS on SCs.
Possible mechanisms for the effects of PM exposure on progenitor/stem cells There is growing evidence that supports an important role of oxidative stress in response to air pollution in different organ systems [113]. Reactive oxygen species could function as signalling molecules in PM 2.5 -trigged autophagy in human epithelia A549 cells [114]. Oxidative stress could be triggered by PM 2.5 and result in alterations in mitochondrial gene expression in brown adipose tissue [115]. Clinical studies suggested that ROS formation, oxidative stress and inflammation induced by PM 2.5 exposure were closely related to paediatric asthma [116]. A relationship has been observed between ambient PM 10 , oxidative burden and carotid intima-media thickness (a change and indicator for subclinical atherosclerosis) [117]. Studies, using a simulated respiratory tract lining fluid model with three major water soluble antioxidants (glutathione, urate and ascorbate) at physiological concentrations that served as the first-line defence in the airway against the oxidative activity of PM, showed that PM could deplete the antioxidants [118]. It was also demonstrated that a close relationship was present for ultrafine particles and NO 2 /NO x [119].
Reactive oxygen species and oxidative stress are involved in EPCs dysfunction in many disease states including hyperlipidaemia, DM and CAD [13,15,44]. It was observed that the functional impairment of human EPCs by diesel exhaust particles was associated with an increased superoxide production [120]. We also observed that ROS production was significantly increased in the EPCs and BMSCs from the mice exposed to PM. Blockage of ROS formation using pharmacological agent NAC or transgenic model with overexpression of NOA effectively prevented PM-induced decrease in the numbers of circulating EPCs and BMSCs. These data suggested that ROS formation was an important cause for decreased number of EPCs [19] and BMSCs following PM exposure (Fig. 1).
Particulate matter exposure was shown to suppress VEGFinduced Akt activation and endothelial nitric oxide synthase (eNOS) phosphorylation in the aorta, and prevented VEGF/AMD3100-induced mobilization of EPCs into the peripheral circulation without change in the plasma levels of human SDF-1a and VEGF [17,66]. Second-hand smoke exposure was also reported to block VEGF-stimulated nitric oxide production [121]. There are extensive and complex interactions between ROS and Akt pathway in both normal and cancer cells. We observed that PM exposure inhibited BMSC proliferation via ROSmediated mechanism(s) partially through suppression of Akt signalling. It is certainly possible that other pathways might also be affected by PM exposure. Future studies are needed to define the role of other pathways in the effect of PM exposure on BMSCs and progenitor cells.

Clinical implications for PM-induced detrimental effects on progenitor/stem cells in cardiovascular system
It is clear that exposure to PM increases the risk of cardiovascular diseases with ROS formation as the predominant mechanism. It could be ideal to avoid inhaling PM physically via wearing masks or using filters. However, fine PM such as PM 2.5 is very difficult to be removed or isolated from the air because of their extremely small size, especially in those cities with severe air pollution. Moreover, PM 2.5 widely exists in the environment and may carry ROS within gas phase [122] or water phase (aerosol) [123] into the lower respiratory tract to create an increased risk for adverse cardiovascular events.
Antioxidant enzyme and antioxidant supplementation have been examined for its impact on cardio-respiratory effects of PM 2.5 exposure. Animal studies have shown an increase in the levels of antioxidant gene expression in epithelial cells after exposure to diesel exhaust particles [124]. It was reported that omega-3 polyunsaturated fatty acid could attenuate the adverse effect of PM 2.5 on heart rate variability [125]. Antioxidant supplementation such as vitamin C and E was shown to have beneficial effects against human lung damage by air pollution [126]. Antioxidant probucol could reduce CS-induced impairment of neovascularization associated with improved function of EPCs [127]. Inhibition of ROS accumulation/production or oxidative stress with pharmacological agents like NAC and SOD-mimics, or overexpression of antioxidant enzymes like Hsp20 and SOD could reduce ROS accumulation in human MSCs, and attenuate oxidative cell damage in BMSCs in vitro [128], protect stem cells against ROS-induced apoptosis in vitro [129], protect MSCs against cell death triggered by oxidative stress in vitro in association with enhanced Akt activation and increased secretion of growth factors (such as VEGF, fibroblast growth factor-2, and insulin-like growth factor 1) [130], increase the differentiation of EPCs into endothelial cells [131], inhibit cell senescence in HSCs in the BM [132] and restore the impaired self-renewal potential and functional activity of HSCs with high ROS level [133]. N-acetylcysteine treatment also protected BMSCs against the toxic effect of low concentration ox-LDL, and restored their endothelial differentiation potential impaired by ox-LDL [134]. Recently, we observed that after PM ≤4 exposure, NAC or overexpression of AON could completely block intracellular ROS production in BMSCs, partially restore p-Akt level, decrease serum TNFa and IL-1b level, reduce EPCs apoptotic rate, effectively reversed the decreased proliferation rate of BMSCs and increased the BMSCs and EPCs number to normal level [19]. Thus, inhibition of ROS production and oxidative stress might be an effective option to ameliorate PMinduced detrimental effects on progenitor cells and SCs as well as cardiovascular system.

Other considerations
There is no question that PM exposure has significant impact on the number and function of progenitor cells and stem cells. However, studies are needed to address a variety of important issues in this area including (but not limited to): (i) determining the size and active components of PM that are responsible for detrimental effect of PM exposure on progenitor cells and SCs, as well as cardiovascular diseases and related mechanism(s) since the size and components are critical to the action of PM [135]; and (ii) defining the mode of actions (direct or indirect) for PM exposure on the progenitor cells and SCs.
The number and function of progenitor cells and SCs are associated with other factors and cells like monocytes and platelets through a wide range of cytokines and growth factors [136][137][138][139]. Both monocytes and platelets are important to cardiovascular physiology (like angiogenesis and haemostasis), and closely related to cardiovascular diseases like CAD. It is known that monocytes display certain plasticity and could function as pluripotent stem cells with regenerative capability, and produce a variety of cytokines and inflammatory fac-tors [140,141]. Particulate matter exposure could exhibit its effects on progenitor cells and SCs through functional and/or structural modifications of monocytes and platelets. Indeed, PM exposure is able to significantly alter the function and responses of platelets both in vitro and in vivo including induction of Ca(2+) release, dense granule secretion and surface expression of platelet activation markers like Pselectin expression, as well as aggregation, and change in the mean platelet volume [142][143][144][145][146]. Particulate matter exposure/treatment has been shown to modify the function of monocytes significantly including inflammatory response and cytokine production, recruitment and mobilization, and transcriptional and translational modulations of gene expressions in monocytes [135,136,[147][148][149][150][151][152]. Further studies are needed to determine the complex relations between PM exposure, monocyte and platelet function, and progenitor cells/SCs.

Conclusion
In this review, we discussed the adverse effects of PM exposure on cardiovascular diseases with specific effort on PM-induced detrimental impact on progenitor/SCs. Indeed, PM exposure correlated with the reduction in life expectancy primarily via cardiovascular diseases, and the resultant abnormality in the number and function of progenitor/SCs might play an important role in cardiovascular diseases related to PM exposure (Fig. 1). However, there are lots of questions that need to be addressed on PM-induced structural and functional impairment on progenitor/SCs. For example, does PM affect the differentiation potential of BMSCs and how? Does PM affect other SCs and how? All these questions require further studies. Although prevention of ROS formation and oxidative stress might be an effective way to attenuate PM-induced deleterious effects on progenitor/SCs, we believe that other mechanisms may be also important for the effect of PM exposure, which merit further investigations. blood pressure responses in healthy adults during controlled air pollution exposures.