Brit. J. Ophthal. (1966) 50, 119

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NOMENCLATURE OF PERICYTES*INTRAMURAL AND EXTRAMURAL

BY

NORMAN ASHTON AND FERRAZ DE OLIVEIRAtDepartment ofPathology, Institute of Ophthalmology, University ofLondon

THE cellular structure of the retinal vessels as revealed by the digest techniquerecently introduced by Kuwabara and Cogan (1960) has aroused widespread interestand speculation, especially concerning the nature and function of the cells to befound embedded in the walls of the retinal capillaries. Cogan and his colleagues atfirst thought that these were the nuclei of perivascular glia, but later concluded thatthey were special cells confined to the retinal circulation (Kuwabara and Cogan,1963), wherein they were probably concerned in the control of capillary blood flow,and, being selectively injured in diabetic retinopathy, were of significance in itspathogenesis (Cogan, Toussaint, and Kuwabara, 1961). Believing that these cellswere an entity not previously described they gave them the special name of "muralcells", a term which is already becoming established in the literature as a specificcomponent of the retinal capillaries.From our own observations and from a review of the literature, it has since become

clear that this cell is not in fact unique to the retina, but corresponds to one type ofcell found throughout the vascular system, and long classified under the confusingterm of "pericyte". It has now become essential, not only in ophthalmologicalwork, but also in general vascular studies, to clarify the nomenclature and select aterm that accurately describes these cells wherever they may be found.

Evidence from Light MicroscopyAlmost all authors from the earliest studies agree that there are two kinds of cell

related to the capillary structure: those which form the endothelium and others inclose relation to the outer wall, which have been discussed for almost a century.Rouget (1873, 1874, 1879) called the latter cells "non-pigmented adventitial cells" or"cells with ramified protoplasmic processes" and attributed to them a specificcontractile function. His study was a careful and extensive one carried out on awide range of specimens including frogs, rabbit and sheep embryos, kittens, puppies,

* Received for publication September 23, 1965.t NATO Fellow on leave from the Institute of Ophthalmology Dr. Gama Pinto, University of Lisbon, Portugal.

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120 NORMAN ASHTON AND FERRAZ DE OLIVEIRA

adult sheep, and the meningeal vessels of embryo calves. He demonstrated thesecells in all tissues studied and, in the present context, it is interesting that he illustratedthem in the hyaloid and capsulo-pupillary membranes of sheep embryos, and inhuman and rabbit retinae. From his illustrations (see Figure) it is clear that thesecells are morphologically identical with the "mural cells" of Kuwabara, Carroll, andCogan (1961).

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FIGURE.-Reproduction of Plate 24 from the classical work of Rouget (1873)showing adventitial cells (intramural pericytes) in various vessels. Fig. 2, inthe capsulo-pupillary vessels of the hyaloid system of sheep embryo (note alsoretraction of vessel); Fig. 3, in new-formed capillaries of sheep embryo;Fig. 4, in the yolk sac of rabbit embryo; Fig. 6, in a retinal capillary of rabbit;and Figs 7 and 8, in adipose tissue of rabbit.

(By courtesy of the British Museum.)

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NOMENCLATURE OFPERIC YTES

Vimtrup (1922) named them "Rouget cells", agreeing that they had a contractilefunction (it may be noted in passing that this view was subsequently vigorouslydenied by others, while today it is the general consensus of opinion that capillariesare non-contractile (Wiedeman, 1963)). The term "pericyte" was applied to thesecells by Zimmermann (1923). Without electron microscopy, however, none of theseauthors could have appreciated the exact location of these cells, and the name"pericyte" has subsequently caused considerable confusion, having been applied notonly to cells with the morphological and topographical characteristics describedby Rouget, but also to many different types of pericapillary cells.

Evidence from Electron MicroscopyWith the advent of the electron microscope the true structure of the capillary was

gradually revealed, so that capillaries are now known to be formed by a continuouslayer of endothelial cells surrounded externally by basement membrane. Insidethis membrane there are situated, at intervals, cells with ramifying protoplasmicprocesses, which surround the capillary and protrude from its outer wall. Farquharand Hartmann (1956) reported them for the first time in electron microscopy of ratbrain and called them "intramembranous pericapillary cells", and shortly afterwardsthey were described, again in the rat brain, by Maynard, Schultz, and Pease (1957).Maeda (1958, 1959) first described them in an electron microscopical study of thehuman retinal vessels, and referred to them as "pericytes". Since that time similarcells, described as "Rouget cells", "pericytes", "pericapillary cells", "perivascularcells", "adventitial cells" or "undifferentiated cells", have been demonstrated by theelectron microscope in the retina (Bernstein, 1961; Bloodworth, 1962; Missotten,1962; Hogan and Feeney, 1963; Ishikawa, 1963; Kuwabara and Cogan, 1963; andothers); in the iris (Ikui, Mimatsu, Maeda, and Tomita, 1960; Tomita, 1960;Missotten, 1964); in the human corneal limbus (Iwamoto and Smelser, 1965); in thebrain of human embryos (Dahl, 1963); in the rat and dog brain (Donahue andPappas, 1961; Hills, 1964; Freeman, 1964); in rat muscle (Majno and Palade, 1961;Freeman, 1964); in human and rabbit connective tissue (Movat and Fernando,1964); and in the capillaries of rat pancreas, lamina propria of the guinea-pig epididy-mis, choroid rete of fish eyes, and in capillaries from Amia and rete mirabile of thefish swim bladder (Fawcett, 1963).

Identity with "Mural Cells"That these cells reported by electron microscopists are the same as those described

by Kuwabara and Cogan (1960); Kuwabara, Carroll, and Cogan (1961); Cogan,Toussaint, and Kuwabara (1961); and Kuwabara and Cogan (1963) can hardly bedoubted, for their location and ultrastructure are identical. Moreover, in our ownstudies in collaboration with Dr. M. Shakib we have seen them by electron microscopyin the iris, conjunctiva, retina, and brain, and by light microscopy in the retina, opticnerve, conjunctiva, brain, meninges, skin, and peritoneum, and can confirm theiressential morphological identity.With regard to the distribution of these cells we have found that in capillaries

shaken free from the human brain, the structure and cellular components are almostidentical with those in the retina (Ashton, 1963; Ashton, Kok, and Foulds, 1963);

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indeed, in a study of capillaries of the cerebral cortex, isolated by an acid-watertechnique, it was found that a slightly greater number of "mural cells" exist in thesecapillaries than in the retina (Oliveira, 1964, 1965); their shape, staining properties,and regular distribution, however, were exactly similar. The same is true of thesecells in the capillaries of the optic nerve and spinal cord, and they have recentlybeen demonstrated in comparable numbers in the tunica vasculosa lentis of thehuman foetus (Mutlu and Leopold, 1964), and in the hyaloid system of the ratling(Agrawal, 1964). Capillaries cannot so effectively be studied in other tissues, butin flat preparations of conjunctiva, dermal and peritoneal connective tissue we havefound similar cells; here, however, they were less regularly disposed than in thenervous system and showed some variation in shape. The very definite encap-sulation of these cells within the basement membrane of the capillaries of the centralnervous system is probably related to the fact that here the basement membrane is awell-defined entity, being delineated internally by the plasma membrane of theendothelial cells, and externally by the plasma membrane of the glia, whereas inother tissues with an ample extracellular space, the basement membrane may fadediffusely into the perivascular tissue depriving the "mural cell" of a compact outerenvelope. It is thus possible that some cells of the same nature may be tenuouslycovered or even uncovered by basement membrane. This may explain why thesecells are relatively poorly developed in the rabbit retina (Mutlu and Leopold, 1964)where most of the vessels are on the surface of the retina and possess a poorly definedbasement membrane. By definition one would not, of course, expect to find "muralcells" in vessels devoid of basement membrane-as in the hepatic sinusoids (Hampton,1958) or in developing vessels.The statement by Kuwabara and Cogan (1963)-"we are unable to state whether

or not mural cells comparable to those in the retinal capillaries exist elsewhere inthe body"-can now, therefore, be answered in the affirmative, and all the evidencesuggests that these cells are those originally described by Rouget in 1873 as "non-pigmented adventitial cells".

NomenclatureWe are not concerned in this paper with the derivation, function, or pathology of

these cells, but only with their nomenclature. In previous papers we continued touse the non-committal term "pericyte" and deferred the adoption of "mural cell"until we were convinced that it was a new entity, but now that it is abundantlyevident that it is not peculiar to the retina, the nomenclature of these cells as a wholeneeds revising.

In the light of the evidence provided by electron microscopy we can no longercontinue to call these cells within the basement membrane "pericytes", "peri-capillary", or "perivascular cells", not only because these names confuse them withcells outside the capillary, but also because they are not sufficiently descriptive.Nor do we feel that the name "mural cell" is ideal, because it has erroneously cometo mean a special retinal entity.A nomenclature is required which accurately describes the situation of these cells

wherever they may be found in the circulation, yet retains an association with retinal

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NOMENCLATURE OFPERICYTES 123

studies and is not so completely new as to confuse the situation further. We con-sider that the terms "intramural pericyte" (encircling cell within the wall) for "muralcell", and "extramural pericyte" (encircling cell outside the wall) for pericytes outsidethe vessel, provide the best nomenclature yet introduced (Rees and others, 1964).The name "pericyte" could then be used as a general term for both types. Thisnomenclature will therefore be used in all our subsequent papers on this subject, andwe trust that others engaged in cognate work, whether ocular or extra-ocular, willconsider it worthy of adoption.

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Press.BLOODWORTH, J. M. B. (1962). Diabetes, 11, 1.COGAN, D. G., TOUSSAINT, D., and KUWABARA, T. (1961). Arch. Ophthal. (Chicago), 66, 366.DAHL, V. (1963). Dan. med. Bull., 10, 196.DONAHUE, S., and PAPPAS, G. D. (1961). Amer. J. Anat., 108, 331.FARQUHAR, M. G., and HARTMAN, J. F. (1956). Anat. Rec., 124, 288.FAWCETT, D. W. (1963). In "Peripheral Blood Vessels" (ed. J. L. ORBISON and D. E. SMITH), pp. 17-44.

Baltimore, Williams and Wilkins.FREEMAN, J. A. (1964). "Cellular Fine Structure", New York, McGraw-Hill.HAMPTON, J. C. (1958). Acta anat. -(Basel), 32, 262.HILLS, C. P. (1964). Amer. J. Path., 44, 531.HOGAN, M. J., and FEENEY, L. (1963). Invest. Ophthal., 2, 101.IKUI, H., MIMATSU, T., MAEDA, J., and TOMITA, I. (1960). Kyushu J. med. Sci., 11, 113.ISHIKAWA, T. (1963). Invest. Ophthal., 2, 1.IWAMOTO, T., and SMELSER, G. (1965). Ibid., 4, 815.KUWABARA, T., CARROLL, J. M., and COGAN, D. G. (1961). Arch. Ophthal. (Chicago), 65, 708.

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MAEDA, J. (1958). Acta Soc. ophthal. jap., 62, 1002.(1959). Jap. J. Ophthal., 3, 37.

MAJNO, G., and PALADE, G. E. (1961). J. biophys. biochem. Cytol., 11, 571.MAYNARD, E. A., SCHULTZ, R. L., and PEASE, D. C. (1957). Amer. J. Anat., 100, 409.MISSOTTEN, L. (1962). Ophthalmologica (Basel), 144, 1.

-(1964). Bull. Soc. belge Ophtal., No. 136, p. 28.MOVAT, H. Z., and FERNANDO, N. V. P. (1964). Exp. molec. Path., 3, 98.MUTLU, F., and LEOPOLD, I. H. (1964). Arch. Ophthal. (Chicago), 71, 102.OLIVEIRA, F. (1964). Arch. port. Oftal., 16, no. 2, p. 87.

(1966). Brit. J. Ophthal., 50, 134.REES, S. B., CAMERINI-DAVALos, R. A., CAULFIELD, J. B., LOZANO-CASTANEDA, O., CERVANTES-AMEZCUS, A.,

TATON, J., POMETTA, D., KRAUTHAMMER, J. P., and MARBLE, A. (1964). In "Colloquia on Endo-crinology" (CIBA Foundation) (ed. M. P. CAMERON and M. O'CONNOR), vol. 15, p. 315. Churchill,London.

ROUGET, C. (1873). Arch. Physiol. norm. path., 5, 603.(1874). C.R. Acad. Sci. (Paris), 79, 559.(1879). Ibid., 88, 916.

TOMITA, I. (1960). Acta Soc. ophthal. jap., 64,,1447.VIMTRUP, B. (1922). Z. Anat. Entwickl.-Gesch., 65, 150.WIEDEMAN, M. P. (1963). In "Handbook of Physiology", Sect. 2: "Circulation" (ed. W. F. HAMILTON and

PHILIP Dow), vol. 2, p. 891. American Physiol. Soc., Washington.ZIMMERMANN, K. W. (1923). Z. Anat. Entwickl.-Gesch., 68, 29.

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