Jennifer K. Lang and Thomas R. CimatoAtherosclerosis

Cholesterol and Hematopoietic Stem Cells: Inflammatory Mediators of

published online March 19, 2014Stem Cells Trans Med 

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Perspectives

Cholesterol and Hematopoietic Stem Cells: Inflammatory Mediatorsof Atherosclerosis

JENNIFER K. LANG, THOMAS R. CIMATO

Clinical and Translational ResearchCenter, Department ofMedicine/Cardiology, School ofMedicine andBiomedical Sciences, StateUniversity ofNewYork

at Buffalo, Buffalo, New York, USA

Key Words. Adult hematopoietic stem cells x CD341 x Cardiac x Hematopoietic stem cells x Hematopoietic progenitors

SUMMARY

Atherosclerosis causing heart attack and stroke is the leading cause of death in the modern world. Therapy for end-stage atheroscleroticdiseaseusingCD341hematopoietic cellshas shownpromise inhumanclinical trials, and the invivo functionofhematopoieticandprogenitorcells in atherogenesis is becoming apparent. Inflammationplays a central role in the pathogenesis of atherosclerosis. Cholesterol is amodifi-able risk factor in atherosclerosis, but in many patients cholesterol levels are only mildly elevated. Those with high cholesterol levels oftenhaveelevatedcirculatingmonocyteandneutrophil counts.Howcholesterol affects inflammatorycell levelswasnotwell understood.Recentfindings have providednew insight into the interaction among hematopoietic stem cells, cholesterol, and atherosclerosis. Inmice, high cho-lesterol levels or inactivation of cholesterol efflux transporters have multiple effects on hematopoietic stem cells (HSPCs), including pro-moting their mobilization into the bloodstream, increasing proliferation, and differentiating HSPCs to the inflammatory monocytes andneutrophils that participate in atherosclerosis. Increased levels of interleukin-23 (IL-23) stimulate IL-17 production, resulting in granulocytecolony-stimulating factor (G-CSF) secretion, which subsequently leads to HSPC release into the bloodstream. Collectively, these findingsclearly link elevated cholesterol levels to increased circulating HSPC levels and differentiation to inflammatory cells that participate in ath-erosclerosis. Seminal questions remain to be answered to understand how cholesterol affects HSPC-mobilizing cytokines and the role theyplay in atherosclerosis. Translation of findings in animalmodels to human subjectsmay includeHSPCs as new targets for therapy to preventor regress atherosclerosis in patients. STEM CELLS TRANSLATIONAL MEDICINE 2014;3:1–4

THE IMPORTANCE OF ADVANCING THERAPIES TO PREVENT

ATHEROSCLEROTIC DISEASE

Modern therapies in medicine have significantly reduced the fre-quency of heart attacks, strokes, and peripheral vascular disease,and have improved long-term outcomes. Advances have comefrom simple measures to control the major risk factors that con-tribute to the risk of cardiovascular disease (CVD) events. Theseinclude adequate blood pressure control, smoking cessation pro-grams, and awareness of hypercholesterolemia as amajor risk fac-tor for atherosclerotic disease, all of which have resulted in asteady decline in deaths from CVD. Despite the progress attained,heart attack alone is still responsible for 30% of deaths worldwideand is a greater cause of mortality than cancer [1]. For those whosurvive a heart attack or stroke, the risk of sustaining a second heartattack, stroke, or heart failure is high, resulting in further sufferingand greater health care costs. Improved application of current ther-apies to prevent CVD is a significant objective, and development ofa greater understanding of the causes of atherosclerosis andmechanism-based therapies to prevent its progression and recur-rence remain an important goal. The next advance in the preventionof atherosclerosis, and its progression, will come from a greater un-derstanding of the chronic inflammatory component of coronaryartery disease.

EVIDENCE FOR HEMATOPOIETIC STEM CELLS IN THE PATHOGENESIS

OF ATHEROSCLEROSIS

Many years ago, it was recognized that patients with hypercholes-terolemia had significant elevations in neutrophil and monocytenumbers in the bloodstream [1], and that higher neutrophil levelswere associatedwith higher risk of heart disease events [2]. The sig-nificance of this finding was pursued by several subsequent investi-gations. Hypercholesterolemia promotes migration of monocytesinto atherosclerotic lesions [3]. Diet-induced hypercholesterolemiain mice results in release of monocytes identified by expression ofCD11b (mice) orCD162CD141monocytes (humans) [4] anddirectlycontributes to the progression of atheroma. In animalmodels of hy-percholesterolemia, the quantity of monocytes in the bloodstreampositively correlates with atherosclerotic lesion size [5]. Neutrophilsand their secreted factors play an important role in the early phasesof atherosclerosis [6], and clinical studies correlating systemic neu-trophil countswith severity of atherosclerosis in humans support anassociationofneutrophilswithdiseaseprogression[7,8].These find-ings suggest a stimulatory effect of cholesterol on hematopoieticstem cells and their progenitors. Although it is known that hemato-poietic stemcells circulate throughout thebody toprovidean immu-nosurveillance response to inflammatory signals [9], it remainedunclear whether cholesterol had a primary effect of mobilizing

Correspondence: Thomas R. Cimato, M.D., Ph.D., State University of New York at Buffalo, School of Medicine and Biomedical Sciences, Department ofMedicine/Cardiology, Clinical andTranslational ResearchCenter, 875Ellicott Street/Suite 7030, Buffalo,NewYork14203,USA. Telephone: (716)829-2663;E-Mail: tcimato@buffalo.edu Received November 24, 2013; accepted for publication January 6, 2014. ©AlphaMed Press 1066-5099/2013/$20.00/0;http://dx.doi.org/10.5966/sctm.2013-0205

STEM CELLS TRANSLATIONAL MEDICINE 2014;3:1–4 www.StemCellsTM.com ©AlphaMed Press 2014

PERSPECTIVES

http://stemcellstm.alphamedpress.org/cgi/doi/10.5966/sctm.2013-0205The latest version is at Published Ahead of Print on March 19, 2014 as 10.5966/sctm.2013-0205

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hematopoietic stemcells into the circulation or to promoting local-ized growth and differentiation within sites of inflammation inatherosclerosis.The contribution of hematopoietic stem cells (HSCs) to athero-

sclerosis remained obscure until recently. Robbins et al. deter-mined that the spleen represents a reservoir of hematopoieticprecursors that generate monocytes that home to atheroscleroticlesions in the aorta [10]. Dutta et al. later identified the source ofthe hematopoietic precursors as KSL1 HSCs [11]. Remarkably, ath-erosclerosis accelerates after myocardial infarction in ApoE2/2

mice with atherosclerotic lesions providing a potent stimulus forrelease of HSCs from the bonemarrow. HSCs then seed the spleenand provide a reservoir of new monocytes that accelerate ather-oma formation. The spleen provides a source of IL-3 and granulo-cyte macrophage colony-stimulating factor (GM-CSF) to promotethe proliferation and differentiation of monocyte precursors tomonocytes.The findingsprovidekeyevidencethat inthehypercho-lesterolemic state KSL1 HSCs are liberated to bone marrow andreside in the spleen where they contribute to extramedullarymonocyte production that contributes to atheroma formation.Interestingly, Psaltis et al. found that the adventitial layer of the

aorta is a source of rare HSCs and a more frequent population ofmacrophage precursor cell types [12]. In the hypercholesterolemicApoE2/2mousemodel, the numbers of HSCs and colonies ofmac-rophages were significantly higher than those in normal animals,suggesting a role for cholesterol in seeding of HSCs and macro-phage precursors to the aorta. Although it is unclear whetherthe HSCs and macrophage precursors directly participate in ather-oma formation, this finding indicates that the state of high choles-terol increases the number of KSL1 HSCs that reside in peripheraltissues and have a preferential differentiation potential to the my-eloid lineage. Collectively, the evidence provided by studies fromDutta et al. [11] and Psaltis et al. [12] indicates that HSCs are mo-bilized to the spleen and aorta and augment monocytic differentia-tion. These findings suggest a role for cholesterol in themobilizationandproliferationofHSCs.Thefindingsalsoindicatethatextramedul-lary myelopoiesis is an important contributor to atherosclerosis.

REGULATION OF HEMATOPOIETIC STEM CELL PROLIFERATION AND

MOBILIZATION BY CHOLESTEROL

Three studies consistently illustrate the principle that cholesterollevels increase the quantity of hematopoietic stem cells in thebloodstream. In wild-type mice fed a high-cholesterol diet fora 30-day period, Gomes et al. showed that elevated cholesterollevels increased the numbers of neutrophils, lymphocytes, andhematopoietic stem and progenitor cells in the bloodstream byincreasing proliferation of bonemarrowcells andpromoting theirrelease from the bone marrow by increasing SDF-1 levels in pe-ripheral blood [13]. In the low-density lipoprotein (LDL) receptorknockout (LDLR2/2)mousemodel, Feng et al. similarly found thathigh-fat diet consumption combined with the LDLR2/2 back-ground increased total cholesterol levels more than ninefold,and LDL cholesterol levels increased 40 times greater thanwild-type animals [14]. The increases in total and LDL cholesterollevels in the bloodstream resulted in a twofold increase in thenumber of c-kit1 Sca-11 Lin2 (KSL1) hematopoietic stem cellsin the bone marrow and a larger increase in KSL1 cells in thebloodstream. The investigators further showed that LDL choles-terol promoted proliferation of KSL cells and augmented

differentiation to monocytes and granulocytes, whereas high-density lipoprotein cholesterol opposed the effects of LDLcholesterol.Additional insights into the impact of cholesterol on hemato-

poietic stem cell biology come frommice with defects in choles-terol efflux pathways due to inactivation of ATP-bindingcassette transporters ABCA1 and ABCG1. These two proteinsmediate efflux of cellular cholesterol to lipid poor ApoA-1 andhigh-density lipoprotein cholesterol. ABCA12/2 ABCG12/2

mice therefore represent an important model to understandhow cholesterol impacts the biology of hematopoietic stem cellsthrough a mechanism unrelated to supraphysiologic levels ofcholesterol or dietary effects. Importantly, ABCA12/2 ABCG12/2

mice show accelerated atherosclerosis in hypercholesterolemicbackgrounds and infiltration of various organs with macrophagefoam cells [15]. ABCA12/2 ABCG12/2 mice remarkably displayleukocytosis and a dramatic greater than twofold expansion ofKSL1 HSCs in the bone marrow. The effects of ABCA12/2

ABCG12/2 on proliferation are due to an increase in membranecholesterol, resulting in increased cell-surface expression of thecommon b subunit of the IL-3/GM-CSF receptor leading to in-creased sensitivity to IL-3 andGM-CSF signals and enhanced pro-liferation [16]. In conclusion, the experiments from the ABCA12/2

ABCG12/2nullmousemodel indicate that intracellular cholesterolaccumulation results in cell intrinsic effects to promote HSCproliferation.

CHOLESTEROL METABOLISM INTERSECTS THE IL-23 IL-17 G-CSF

AXIS IN HEMATOPOIETIC STEM CELL MOBILIZATION

The ABCA12/2 ABCG12/2 mouse model provides additionalinsights into the mobilization of KSL1 HSCs into the blood-stream. Westerterp et al. found that ABCA12/2 ABCG12/2

knockout animals had threefold higher levels of KSL1 HSCs inthe bloodstream and in the spleen, indicating increased mobili-zation of HSCs from the bone marrow [17]. Mechanistically,ABCA12/2 ABCG12/2 knockout mice had greater than twofoldincreased granulocyte colony-stimulating factor (G-CSF) levelsin the bloodstream, mediating the mobilization of HSCs frombonemarrow. Precisely howG-CSF secretion is regulated by dis-ordered cholesterolmetabolism is unclear. G-CSF secretion is in-ducedby IL-17producedbyT cells, and indeed IL-17-neutralizingantibodies decreased G-CSF levels in the blood of ABCA12/2

ABCG12/2 mice, suppressing HSC mobilization. A previouslycharacterized homeostatic mechanism regulating granulopoie-sis was described in which macrophages and dendritic cells se-crete IL-23 to augment neutrophil production when phagocyticactivity of apoptotic neutrophils is reduced because of low neu-trophil counts in tissues [18]. IL-23 then acts on T cells to induceproduction of IL-17, which induces G-CSF secretion and mobili-zation of HSCs frombonemarrow stores. Infusionwith recombi-nant HDL cholesterol reduced serum IL-17 and G-CSF levels,leading to lower levels of HSCs in the bloodstream, and reversedthe effects of ABCA12/2 ABCG12/2 knockout. These findingshighlight the role of the IL-23 IL-17 G-CSF axis in mobilizationof HSCs, and suggest a role for cholesterol in regulation ofHSC mobilization. The cholesterol-sensitive component of thecell mobilization pathway may represent a novel approach totherapy in atherosclerosis by reducing cholesterol-induced HSCmobilization.

2 Cholesterol, HSCs, Atherosclerosis

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LINKS BETWEEN CHOLESTEROL LEVELS AND CIRCULATING HSPCS

IN HUMANS

Variation in CD34 Levels by Cholesterol, MyocardialInfarction, and Stroke

Although the findings in the mouse models described above areauseful starting point todevelopnewapproaches toprevent and re-gress atherosclerosis, it is important to note that the degree of hy-percholesterolemia found in murine models of atherosclerosis issubstantially higher than that found in humans. For example, Fengetal. foundthatLDLR2/2mice fedanormaldiethadtotal cholesterollevels of 1006 9.6 mg/dl and LDL cholesterol levels 446 8.4 mg/dl[14]. Upon feeding the mice a high-fat diet, total cholesterol levelsincreased roughly 5-fold and LDL cholesterol levels 10-fold. In con-trast,most human subjectswho sustain amyocardial infarction havetotal cholesterol levels ranging between 200 and 250 mg/dl. Conse-quently, the degree of cholesterol elevation in the murine model iswell above the levels normally found in humans. Therefore, it is im-portant that verifying studies confirm the findings of HSC mobiliza-tion and quantity in the bloodstream, and determine whetherthere is any correlation between cholesterol and HSC levels.The quantity of CD341 cells in the bloodstream of humans has

been the subject of numerous studies under varying contexts.CD34 expression by itself in humans identifies several cell types in-cluding hematopoietic stem and progenitor cells [19], angiogeniccells [20], and endothelial colony-forming cells [21]. The quantityof CD341 cells in the bloodstream has been used as an assessmentof vascular health, as well as an important source of cell therapy forpatients with ischemic heart and limb diseases. The largest study tomeasure the levels of CD34-expressing cells in the bloodstream ofhumansanddetermine the clinical andgenetic parameters that reg-ulate their numbers was performed by Cohen et al. as part of theFramingham Offspring Study [22]. In that study, 1,786 subjects un-derwent clinical assessmentanddeterminationofCD34cell levels inthe bloodstream by flow cytometry. Correlations between CD341

cell numbers in the bloodstream and clinical parameters were de-termined. Positive effects on CD34 numbers after multivariate ad-justment included weight, total cholesterol levels, and HMG-CoAreductase inhibitor use, and age, sex, and cigarette smokingcorrelatedwith reducedCD341 cell levels in the bloodstream. Re-markably, the clinical parameters assessed accounted for only 6.3%of the variability in CD341 cell numbers. CD341 cell quantity wasfound to be highly heritable with a high degree of correlation inCD341 cell numbers between siblings but not between spouses.The study is the only large-scale study of its kind to assess CD341 cellnumbers in the bloodstream, but the study cohort had relatively lowcholesterol levels compared with those of subjects with myocardialinfarcts and only measured CD341 cells with no costainingmarkers.Severaldifferent populations of CD341cells in thebloodstreamare

of clinical relevance in heart disease and tissue repair.Massa et al. de-termined the quantity of more specific subpopulations of CD34 celltypes including CD341CD331andCD341CD381hematopoietic pro-genitors and CD341CD1331VEGFR21endothelial progenitor cells inthe setting of acute myocardial infarction (AMI) [23]. Of note, theCD1331VEGFR21cells have been identified as a population of angio-genicmonocytes [24]. The investigators foundno change in the levelsof CD341 CD382 hematopoietic progenitors after AMI. More differ-entiated hematopoietic progenitor cell types that were CD341 andCD331, CD381 and CD1171, as well as CD341CD1331VEGFR21en-dothelial progenitor cells (EPCs) increased in quantity 5.8-fold after

the onset of symptoms in AMI. Similar increases in blood colony-formingunitswerenoted in theAMIgroupcomparedwithunaffectedcontrol subjects. Interestingly, although the investigators did not re-port specific cholesterol levels in the cohort, they did report that only20% of the AMI population had dyslipidemia. Similar increases inCD341 cell numbers in the bloodstream have been reported inpatients with an acute stroke; however, subfractionation of specificCD341 cell types was not performed to distinguish hematopoieticstem cells, hematopoietic progenitor cells, and EPCs.A recent study by our group aimed to examine the effects of

cholesterol levels on the quantity of CD341 Lineage2 CD45dim

HSPCs in humans using a unique strategy [25]. We modulatedthe levels of cholesterol in human subjects with no known historyof atherosclerosis using three statins of differing potencies for a2-week treatment duration. The quantity of CD341HSPCs was de-termined after treatment. All three statin treatments reduced thequantity of CD341HSPCs, and CD341HSPC levels positively corre-lated with serum LDL cholesterol levels. Mechanistically, LDL cho-lesterol increases the number of CD341HSPCs in the bloodstreamby increasing proliferation, and by increasing the levels of mobiliz-ing cytokines IL-17 and G-CSF. The findings provided confirmatoryevidence for the mechanism defined by studies in ABCA12/2

ABCG12/2 knockout mice, in which increased IL-17 and G-CSF lev-els mobilized KSL1 HSCs in mice. How cholesterol levels modulateIL-17 levels remains to be determined but may represent an ad-ditional target to reduce activation of inflammatory cells inhypercholesterolemia.IL-17 is producedprimarily byT cells,whichare knowntocontrib-

ute to atherosclerosis [26]. Although a mechanistic connection be-tween cholesterol levels and IL-17 remains to bedetermined, IL-17–producing TH17 cells and counter-regulatory Treg cells appear tobecome imbalanced in acute coronary syndromes. A recent studybyMa et al. identified a significant increase in the numbers of IL-17-producing TH17 cellswith corresponding reductions in Treg cell typesthroughan increase in IL-6 levels inpatientswithacutecoronarysyn-dromes [27].Asnoted in thestudiesdescribedabove,HSPCsaremo-bilized in animal models of myocardial infarction and contribute tothe progression of atherosclerosis after a heart attack. The IL-17 G-CSF axis appears to stimulate themobilization of HSPCs in bothmiceand humans, and IL-17-producing T-cell subsets are augmented inmyocardial infarction, representing a potential but unexplored tar-get to block the inflammatory component of atherosclerosis.

CONCLUSION

The interaction of cholesterol, hematopoietic stem cells, and the in-nate immunesystemhas remainedsomewhatunclearuntil recently.Translation of the connection between cholesterol and HSCs identi-fied in animal models to human subjects represents an importantavenue to determine whether the biology of humans is the sameand whether antagonism of HSC mobilization and differentiationin response to cholesterol is of benefit for prevention and regressionof atherosclerosis.

AUTHOR CONTRIBUTIONS

J.K.L.: conception and design, manuscript writing, final approvalof manuscript; T.R.C.: conception and design, financial support,manuscript writing, final approval of manuscript.

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

The authors indicate no potential conflicts of interest.

Lang, Cimato 3

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4 Cholesterol, HSCs, Atherosclerosis

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