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(The FASEB Journal. 2003;17:592-597.)
© 2003 FASEB

Cellular origins of atherosclerosis: towards ontogenetic endgame?

TERENCE M. DOHERTY, PREDIMAN K. SHAH and TRIPATHI B. RAJAVASHISTH1

Atherosclerosis Research Center, Division of Cardiology, Department of Medicine and the Burns and Allen Research Institute, Cedars-Sinai Medical Center and David Geffen School of Medicine at UCLA, Los Angeles, California, USA

1Correspondence: Atherosclerosis Research Center, Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Davis Research Bldg., Room 1062, 8700 Beverly Blvd., Los Angeles, CA 90048-1865, USA. E-mail: rajavashisth{at}cshs.org


   INTRODUCTION
TOP
 INTRODUCTION
THE CONVENTIONAL MODEL OF...
 AN EMERGING MODEL
 COLLATERAL SUPPORT
 UNANSWERED QUESTIONS
 IMPLICATIONS FOR THERAPY
 REFERENCES
 
CONVENTIONAL WISDOM has successfully chronicled in exquisite detail the complex interplay of pathologic processes leading to the formation of atherosclerotic plaque and neointimal proliferation after arterial injury. Conventional therapy spawned from conventional wisdom has, unhappily, achieved considerably less notable success affecting outcomes of both. Atherosclerosis-based diseases exact a tremendous human and fiscal toll, and the road ahead looks grim: as antibiotic usage in underdeveloped areas of the world accelerates, cardiovascular disease will soon overtake infection as the leading cause of death and disability in the entire world (1 , 2) . To be sure, there have been some clear wins, such as in the case of the efficacy of statin therapy in improving cardiovascular outcomes. But why the mismatch between our understanding of the pathology and our ability to measurably affect its long-term impact? It may now be time to rethink fundamental conceptions regarding the nature of atherosclerosis.


   THE CONVENTIONAL MODEL OF VASCULAR DISEASE
TOP
 INTRODUCTION
 THE CONVENTIONAL MODEL OF...
AN EMERGING MODEL
 COLLATERAL SUPPORT
 UNANSWERED QUESTIONS
 IMPLICATIONS FOR THERAPY
 REFERENCES
 
From within the box, atherosclerosis is a chronic fibroproliferative inflammation of the arterial wall brought about and exacerbated by the dynamic interaction of disordered lipid metabolism and other insults and risk factors with homeostatic mechanisms designed to protect against such injury (3 4 5) . Decades of research have illuminated pathophysiologic details and provided a mechanistic and conceptual framework. Serum lipoproteins diffusing through extracellular space become entangled in the subendothelium and begin to undergo oxidative and covalent modifications that render them proinflammatory. Overlying endothelial cells (ECs) become affected, and the alert goes out. The troops of the immune and mononuclear phagocytic systems converge on the scene, guided by adhesive homing signals expressed by ECs. The ensuing maelstrom of cytokines, growth factors, mitogens, and morphogens instigates smooth muscle cells (SMCs) to migrate from the medial layer into the intima, differentiate toward a synthetic phenotype, and proliferate. But many of the cells recruited to resolve the problem become part of the problem when they find themselves unable (or unwilling) to escape, and in cytotoxic microenvironments they undergo apoptosis and release their proinflammatory contents into the nascent plaque. Some of the SMCs are caught in the cytokine crossfire and succumb (6) , further exacerbating the inflammatory nidus. Additional signals are sent calling for more help, and a vicious spiral of inflammation can then occur. The homeostatic balance between normal proteolytic remodeling and inhibition of extracellular proteolytic activity may be tipped toward excessive tissue destruction (7) . Structural deterioration can result in erosion or rupture of the plaque cap, which directly precipitates arterial thrombosis with frequently disastrous consequences (8 9 10) .

In arterial plaque, there are a number of cell types (among them mononuclear phagocytes, T cells, B cells, natural killer cells, and mast cells), all thought to originate from circulating hematopoietic and immune precursors. But two key cell types—ECs and SMCs—are presumed to be resident arterial cells. Almost three decades ago Benditt and Benditt found that plaques contain a monoclonal population of cells (11) . Work from the Schwartz laboratory and elsewhere confirmed and extended these observations to formulate the monoclonal hypothesis. According to this model, proliferating arterial cells are derived from specific SMC clones (12) or clonal expansion of rare resident arterial progenitor cells in response to specific stimuli (13) . Monoclonal expansion is a frequent feature even of normal arteries (14) , and mutations and derangements of chromosomal architecture are often found in monoclonal cells of a lesion (15 , 16) . These findings even led to the more extreme model that views plaque as a benign SMC tumor in the arterial wall (17) . But all models of atherosclerosis share a heavy reliance upon two pivotal features: increased adhesiveness of ECs, and migration and proliferation of SMCs—both presumed to be resident arterial cells.


   AN EMERGING MODEL
TOP
 INTRODUCTION
 THE CONVENTIONAL MODEL OF...
 AN EMERGING MODEL
COLLATERAL SUPPORT
 UNANSWERED QUESTIONS
 IMPLICATIONS FOR THERAPY
 REFERENCES
 
Stepping away from the box, astonishing recent data suggest that this conceptual framework might be in serious jeopardy. In animal models of atherosclerosis, restenosis, and transplant vasculopathy, Sata and co-workers performed bone marrow transplantation (BMT) experiments by lethal irradiation of recipient mice, followed by intravenous injection of bone marrow cells from donor animals with either an identical or nonidentical genotype (18) . The donor cells were labeled with fluoroprobes or reporters so their fate could be tracked and the origins of lesional cells subsequently ascertained with confidence. To control for possible secondary effects arising from interactions among bone marrow cells, irradiated mice were simply injected with hematopoietic stem cells (HSCs). Regardless of the reporter used (GFP or LacZ), the experimental treatment (irradiation followed by either BMT or injection of HSCs), or the dependent variable (de novo atherogenesis, neointimal proliferation after arterial injury, or cardiac transplantation arteriopathy), the results were the same. The electrifying conclusion: most of the cells (as much as 88%) comprising de novo plaque, neointimal proliferation after arterial injury, and transplant arteriopathy are not resident arterial cells at all, but instead originate from hematopoietic bone marrow, circulate in the blood, and migrate to (or are recruited by) nascent sites of plaque formation (18) . As already noted, it has long been known that immune and mononuclear phagocytic cells originating from hematopoietic marrow are found abundantly in developing plaque, but these investigators showed that ECs and SMCs were also derived from bone marrow.

Shimizu et al. reported similar findings in an animal aortic transplant model (19) . Using a reporter (LacZ) and immunostaining to identify cell type, these investigators reported that most of the intimal SMCs in transplanted aortae originated in the host animal, presumably from the bone marrow. Very few intimal cells had migrated from the media of the anastomosed host aorta. However, the proportion of clearly identified marrow-derived SMCs was less than that reported by Sata et al. (18) . Very recently, Hu et al. transplanted mouse aortae onto carotid arteries and also found that neointimal cells originated from the recipient, not the donor aorta (20) . These investigators found no evidence suggesting SMC migration from the media into the intima of the transplanted aorta, and migration from the recipient carotid artery was ruled out as well. However, it was determined that intimal SMCs did not seem to originate in recipient bone marrow. These authors speculated that the source of intimal SMCs might have been pluripotent cells derived from the recipient liver or microvasculature that migrated to the lesion site via the circulation.

Clarifying studies are needed to address several issues, but collectively these data nevertheless dovetail nicely with evolving concepts of tissue remodeling and repair by pluripotent cells originating from spatially remote regions. Once thought to be largely the purview of resident parenchymal cells, increasing evidence is now consistent with a general model wherein somatic nonresident stem cells are mobilized and recruited to remote sites of injury, where differentiation into the necessary lineages and tissue repair processes then occurs (21 22 23 24) . Circulating bone marrow-derived hematopoietic stem cells have been proposed to be recruited to developing atheromatous lesion sites as well (25 , 26) . The animal studies above will require independent verification, and their generalizability will need to be clarified by investigations using other animal models, particularly since other investigators have reported substantially less bone marrow-derived cells in aortic allograft arteriosclerosis models (27 , 28) . These discrepant results might be due to methodological differences or be related to factors unique to the species and models involved, but the reasons require clarification. That much appears relatively straightforward, but a bigger challenge will be to establish relevance to human pathology.


   COLLATERAL SUPPORT
TOP
 INTRODUCTION
 THE CONVENTIONAL MODEL OF...
 AN EMERGING MODEL
 COLLATERAL SUPPORT
UNANSWERED QUESTIONS
 IMPLICATIONS FOR THERAPY
 REFERENCES
 
Other recent data provide supportive evidence demonstrating that a small but expandable population of cells derived from adult murine or human bone marrow retains the capacity to differentiate into virtually any other stem cell subtype, and thence pursue differentiation pathways far removed from hematopoietic tissues. That is, they are adult marrow cells possessing functional features both in vitro and in vivo characteristic of embryonic stem cells (29) . Together with the animal studies reviewed above, these findings blur de facto boundaries not only between germ layers but between organs, and raise provocative questions concerning the fundamental ontogenetic basis of atherosclerosis in general. Where do vascular cells come from, how and why do they migrate there, what makes them converge on particular locations and not others, and why do they cause lethal lesions in one part of an artery while producing only benign lesions (or no lesion at all) in closely adjacent arterial segments? What are the external and internal cues and signaling events that govern them? Do roaming pluripotent cells patrol arterial tissues in search of areas where healing or tissue regeneration is needed, or are they summoned there? How long do they stay, and what determines their behavior and the fates of their progeny? Are there ready-made niches where they take up residence (30 , 31) , or do they somehow create their own niches upon arrival? Do they indefinitely replenish themselves, is the process temporally self-limited, or terminated by predetermined structural criteria and/or signaling that specifies completion of the task?

The concept that atherosclerosis might be driven less by events strictly localized to arterial microenvironments, but rather by molecular events occurring elsewhere in the body, appears consistent with numerous studies that document wide ontogenetic versatility of pluripotent cells that even crosses traditional germ layer boundaries. For example, mesodermal lineages can originate from ectodermal origins, and ectoderm may give rise to mesodermal tissues (32 , 33) . Bone marrow cells can migrate to sites of necrotizing skeletal muscle injury (34) and there differentiate into cardiac muscle cells (35) , ECs (36) , osteoblasts (37) , liver cells (38 39 40) , and both neuronal (41 , 42) and non-neuronal (33) brain cells. There is evidence that muscle cells can transdifferentiate into hematopoietic lineages (43 44 45 46) ; pancreatic cells have been reported to be capable of generating hepatocytes and vice versa (47 48 49 50 51 52 53 54) , and myoblasts (55 , 56) and fibroblasts (57) can be induced to transdifferentiate into adipocytes. Astonishingly, Krause et al. recently succeeded in completely reconstituting bone marrow in lethally irradiated mice by injecting a solitary HSC (58) . The founder cell then expanded into a progenitor pool that engrafted multiple organs and differentiated into numerous lineages. Bone marrow subsequently harvested from the single-cell recipients could even be used to perform long-term repopulation of irradiated secondary host animals (58) . The homeostatic and pathophysiologic relevance of much of this work remains to be defined, but it is nevertheless increasingly clear that stem cells once thought to be committed progenitors of specific lineages, tissue types, organs, or germ layers possess surprisingly robust ontogenetic plasticity.

The notion that cells in arterial plaque might have diverse or unexpected origins is not altogether new. Vascular SMCs arise embryologically from the neural crest and local differentiation from mesenchyme, but ontogenetic divergence of SMCs from mesenchymal ECs that first lay down a template for a vessel network appears to be an early event (59) . DeRuiter and colleagues have reported that vascular ECs can delaminate, migrate into the subendothelium, and transdifferentiate into SMCs (60) . Other studies have provided evidence for circulating endothelial progenitor cells in the peripheral blood of adult animals, and these appear to function in neovascularization and angiogenesis, and perhaps also re-endothelialization of injured arteries (61 62 63) .

The early work of Benditt and Benditt and then Schwartz and others now appears to morph into a much different model of how atherosclerosis and other arterial diseases might arise, a model that at this point is still quite far outside the box, but nonetheless tantalizing. The clonal nature of SMCs, together with their phenotypic uniqueness (13 , 64) and the fact that they are capable of expressing markers characteristic of hematopoietic cells [CD34, Thy-1, c-kit, and flt-3 receptor (65)] are consistent with the conclusion that they originated from hematopoietic precursors. The reports from Shimizu et al. and from Sata et al. provide a glimpse of just how robust this phenomenon might be in explaining the origins of diverse vascular diseases. It will be important to determine whether marrow cells are recruited to the developing plaque in a manner similar to the mechanism of leukocyte recruitment by ECs (66) . It has been proposed that they arrive via adventitial neovascular routes (19 , 20) . But it is also possible that a general tissue surveillance mechanism is operative, wherein multipotent cells enter tissues and organs through more direct routes such as capillaries or microvessels and patrol the area in search of sites of injury.


   UNANSWERED QUESTIONS
TOP
 INTRODUCTION
 THE CONVENTIONAL MODEL OF...
 AN EMERGING MODEL
 COLLATERAL SUPPORT
 UNANSWERED QUESTIONS
IMPLICATIONS FOR THERAPY
 REFERENCES
 
The implications are enormous and suggest that the reductionism inherent in molecular and cellular biologic approaches might have led us far afield: have we spent a half-century describing in exhaustive detail all the trees around us, only to have missed the fact that we are standing in a forest? As is usually the case with seminal findings that break with tradition, there will be a surfeit of speculation but a paucity of empiric evidence for some time to come. Yet the questions that must now be asked are provocative and exciting. Is atherosclerosis less a disease of the artery, more one of the hematopoietic system, or both? What are the stimuli that cause circulating cells to participate in atherogenesis and neointimal proliferation? What are the signaling and feedback mechanisms among bone marrow, blood, and artery? Besides the well-described EC adhesion receptors that facilitate adhesion and transendothelial migration, studies using in vivo phage display biopanning have identified organ-selective peptide sequences that home to diseased vessels, and these could be involved in signaling and homing events (67 , 68) . Could there be additional targeting/homing mechanisms, perhaps in the microvessels and/or neovasculature, and how are they regulated? Could it be that risk factors primarily affect the hematopoietic system and only secondarily and/or indirectly affect the artery?


   IMPLICATIONS FOR THERAPY
TOP
 INTRODUCTION
 THE CONVENTIONAL MODEL OF...
 AN EMERGING MODEL
 COLLATERAL SUPPORT
 UNANSWERED QUESTIONS
 IMPLICATIONS FOR THERAPY
REFERENCES
 
Discarding more rigid conceptions about cell source, differentiation pathways, and tissue and germ layer boundaries may help to begin to equalize the nagging discordance between our understanding of vascular biology and pathobiology and our ability to affect the course of vascular disease. From the standpoint of innovative therapeutic development, the forging of aggressive new alliances with investigators in stem cell biology might enable us to design exciting new treatment paradigms centered around engineering of bone marrow-derived multipotent precursor cells that could potentially be delivered autologously. In fact, such approaches are already being pursued. Examples include the use of gene transfer of vascular endothelial growth factor into endothelial progenitor cells to stimulate neovascularization in ischemia (22 , 69 , 70) and into myoblasts to treat myocardial infarction (71) , but these are only the beginning. One strategy could involve engineering of progenitors to promote plaque stabilization (72) , and this need not require genetic engineering. For example, statins mobilize endothelial progenitor cells (73 , 74) , raising the possibility that pharmacologic strategies might be devised to specifically alter mobilization of progenitors or the relative proportions of pluripotent hematopoietic subfractions. But ultimately the goal would be abrogation or reversal of the disease entirely. To get anywhere within sight of that goal will require a far better understanding of the ontogenetic versatility of pluripotent hematopoietic cells: how they interact with arterial tissues and how they function or malfunction in both homeostatic and pathologic conditions. Toward this end, evidence reviewed here suggests that, at the very least, it may be best to suspend more traditional concepts of cellular source and fate. The more extreme position that these studies bring us ever closer to is that the entire conceptual framework of hard-wired cellular and tissue ontogenetic determinism has outlived its usefulness: we may be approaching ontogenetic endgame. Newly armed with a deeper appreciation of cellular versatility, the road forward now looks to be a journey richly filled with surprise and excitement for some time to come.


   ACKNOWLEDGMENTS
 
Supported by grants from the National Heart, Lung, and Blood Institute (HL51980 and HL58555 to T.B.R.), National Institutes of Health, Bethesda MD. Additional support generously provided by the Mirisch Foundation, United Hostesses Charities, the Eisner Foundation, the Grand Foundation, the Ornest Family Foundation, the Entertainment Industry Foundation, and the Heart Fund at Cedars-Sinai Medical Center, Los Angeles, California. We thank Dr. E. Richard Stanley (Albert Einstein College of Medicine) for his critical review and helpful suggestions.

Received for publication October 7, 2002. Accepted for publication December 19, 2002.


   REFERENCES
TOP
 INTRODUCTION
 THE CONVENTIONAL MODEL OF...
 AN EMERGING MODEL
 COLLATERAL SUPPORT
 UNANSWERED QUESTIONS
 IMPLICATIONS FOR THERAPY
 REFERENCES
 

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T. M. Doherty, K. Asotra, L. A. Fitzpatrick, J.-H. Qiao, D. J. Wilkin, R. C. Detrano, C. R. Dunstan, P. K. Shah, and T. B. Rajavashisth
Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads
PNAS, September 30, 2003; 100(20): 11201 - 11206.
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