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MICROSCOPY RESEARCH AND TECHNIQUE 38:227–236 (1997)
Heterogeneity of Epithelial Cells in the Rat Thymus
ERIC J. DE WAAL1 AND LOUK H.P.M. RADEMAKERS2*
1National
Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands
of Pathology, University Hospital, Utrecht, The Netherlands
2Department
KEY WORDS
thymus; thymic epithelial cells; heterogeneity; immunohistochemistry; transmission electron microscopy
ABSTRACT
The morphological heterogeneity of the thymic epithelium has been well documented both at the light and electron microscopic level. Immunohistochemistry has revealed four
broad classes of epithelial cells (EC): subcapsule/perivascular, cortical, medullary EC, and medullary Hassall’s corpuscles. Ultrastructural analysis has revealed further heterogeneity. In the cortex,
four EC subtypes have been described ultrastructurally: subcapsular/perivascular, ‘‘pale,’’ ‘‘intermediate,’’ and ‘‘dark’’ EC. These subtypes are also present in the medulla. Two additional EC subtypes
are restricted to the medulla: an undifferentiated subtype, and a subtype displaying signs of high
metabolic activity. Based on the morphological features of the epithelium, it has been hypothetized
that the thymic EC subtypes represent a process of differentiation. Microsc. Res. Tech. 38:227–236,
1997. r 1997 Wiley-Liss, Inc.
INTRODUCTION
The thymus is unique among the lymphoid organs in
that the stromal compartment is composed largely of
stationary epithelial cells (EC) (Schuurman, 1988). The
thymic stroma contains among others two additional
cell types: interdigitating dendritic cells (IDC) and
macrophages (Mf) (Boyd et al., 1993; Duijvestijn and
Hoefsmit, 1981; Kendall, 1981, 1991; Ushiki, 1986; Von
Gaudecker, 1991). Immunohistochemically, thymic EC
are characterized by the presence of cytoskeletal keratin intermediate filaments and, at the ultrastructural
level, by the presence of tonofilaments and desmosomes
(Bearman et al., 1978; Colic et al., 1989; Farr and
Braddy, 1989; Hwang et al., 1974; Kampinga et al.,
1989; Kendall, 1981, 1986, 1988; Laster et al., 1986;
Singh, 1981; Van Haelst, 1967; Von Gaudecker, 1991;
Von Gaudecker et al., 1986). The epithelium provides
the three-dimensional framework, within which all
other thymic cell types reside (Bearman et al., 1978;
Hwang et al., 1974).
Involvement in Thymocyte Differentiation
Studies in the neonatal rat thymus have revealed
that EC, IDC, Mf, and thymocytes preferentially occupy defined areas of the thymus, within which they
are distributed and form cell complexes in a nonrandom manner (Brelinska et al., 1985). The cell composition of such complexes is typical and corresponds to
the composition of multicellular complexes released
after the dissociation of the thymic structure by enzymatic digestion as shown by experiments in mice
(Brelinska et al., 1986; Toussaint-Demylle et al., 1991).
Close interaction between the developing thymocytes
and the thymic stroma is essential in intrathymic T cell
differentiation (Boyd et al., 1993). This interaction is
based on cell-cell plasma membrane contacts (Farr et
al., 1985; Müller and Kyewski, 1993; Savion et al.,
1989; Utsumi et al., 1991) and the secretion of soluble
peptidic factors including cytokines by EC and other
r 1997 WILEY-LISS, INC.
thymic stromal cells (Denning et al., 1988; Geenen et
al., 1992; Hadden, 1992; Kendall, 1991; Millington and
Buckingham, 1992; Nabarra and Papiernik, 1991; Ritter and Boyd, 1993; Takahama et al., 1994; Wolf and
Cohen, 1992). A key notion in thymology is that different stromal microenvironments govern distinct events
in T-cell development (Boyd et al., 1993; Ritter and
Boyd, 1993; Van Ewijk, 1988). Despite extensive research, however, the particular functions of individual
stromal elements and their soluble mediators in T-cell
development still are not well understood. To gain more
insight into the heterogeneity of the thymic epithelium,
we identified thymic EC subtypes ultrastructurally and
studied their tissue distribution in the rat thymus.
DISTRIBUTION OF EPITHELIAL CELLS
IN THE THYMUS
Cortical Epithelium
EC in the subcapsular region form a layer of one or
two cells deep. Slightly deeper in the cortex (i.e., in the
outer cortex), thin, sheet-like EC are found displaying
slender cytoplasmic processes. EC in the mid and deep
cortex also have slender cytoplasmic processes providing a large surface area for cell-cell interactions between EC and developing thymocytes (Hoshino, 1963;
Singh, 1981; Van Ewijk, 1988).
Thymic Nurse Cells
In the outer cortex, some EC appear to completely
surround and enclose a large number (about 10–250) of
thymocytes (Boyd et al., 1993). These so-called thymic
nurse cells (TNC) have first been isolated from the
mouse thymus by enzymatic digestion (Wekerle and
Ketelsen, 1980; Wekerle et al., 1980). Later, TNC have
*Correspondence to: L.H.P.M. Rademakers, Ph.D., Division of Histochemistry
and Electron Microscopy, Department of Pathology, Academic Hospital Utrecht,
P.O. Box 85,500, NL-3508 GA Utrecht, The Netherlands.
Accepted in revised form 12 January 1995
228
E.J. DE WAAL AND L.H.P.M. RADEMAKERS
been described in situ in the subcapsular and outer
cortical regions of the human thymus (Dipasquale and
Tridente, 1991; Ritter et al., 1981; Van De Wijngaert et
al., 1983) and the mouse thymus (Andrews and Boyd,
1985; Kyewski and Kaplan, 1982; Leene et al., 1988;
Van Ewijk, 1988). Thus far, TNC have not been recognized as such in the rat thymus (Ushiki, 1986). Hwang
and coworkers (1974), however, have demonstrated
epithelial-lymphoid cell complexes in the rat thymus at
the ultrastructural level, which strongly resemble TNC.
In the human thymus, TNC seem to be localized not
only in the cortex, but also in the cortico-medullary
junction and in the medulla (Dipasquale and Tridente,
1991). Similar observations have been reported in the
mouse thymus by Kaneshima and coworkers (1987),
although these authors point to the difficulty in identifying TNC in situ even by immunoelectron microscopy.
Wekerle and coworkers (1980) have also stressed the
difficulty to demonstrate TNC in situ, because, in the
normal thymus, the epithelium is overcrowded with
thymocytes. In addition, the visualization of TNC is
hampered by the linkage of TNC to adjacent EC,
resulting in the formation of an interlacing network of
EC (Hiramine et al., 1990). TNC isolated from the
mouse thymic medulla, in contrast to cortical TNC,
contain only a small number of thymocytes (ToussaintDemylle et al., 1990). Scanning electron microscopic
images of the mouse thymus have suggested that
thymocytes migrate in or out these lympho-stromal
complexes (Van Ewijk, 1988). TNC are thought to be a
specialized microenvironment involved in T-cell differentiation (Aguilar et al., 1994; De Waal Malefijt et al.,
1986; Dispasquale and Tridente, 1991; Kyewski, 1986;
Lahoud et al., 1993). Although the epithelium is thought
to be a sessile component of the thymus (Kendall, 1991),
the subcapsular epithelium in particular may be a
dynamic structure, since transitional forms have been
observed between sheet-like EC, basket-like EC, and
TNC depending on the type of cortical lympho-stromal
interaction (Van Ewijk, 1988, 1991). TNC may therefore represent the end-stage of a continuum of such
structures from open to completely closed (Boyd et al.,
1993).
Medullary Epithelium
In contrast to the dendritic morphology of cortical
EC, most medullary EC are closely packed displaying
voluminous cytoplasm and short, blunt processes (Duijvestijn and Hoefsmit, 1981; Hoshino, 1963; Singh,
1981; Ushiki, 1986; Van Ewijk, 1988, 1991; Van Ewijk
et al., 1988; Von Gaudecker and Müller-Hermelink,
1980). Whorls of highly keratinized medullary EC,
so-called Hassall’s corpuscles (Kendall, 1981), are particularly well developed in the human thymus (Boyd et
al., 1993; Lobach et al., 1985; Nicolas et al., 1989; Von
Gaudecker and Schmale, 1974; Von Gaudecker et al.,
1986). Depending on the strain involved, in rats and
mice, these structures generally are rarely encountered
and ill developed (Colic et al., 1988a; Duijvestijn and
Hoefsmit, 1981; Hwang et al., 1974; Kendall, 1991;
Lobach et al., 1987; Nicolas et al., 1989; Ushiki, 1986).
Very little is known on the function of Hassall’s corpuscles. It has been postulated that they are graveyards for dead thymocytes (Boyd et al., 1993; De Maagd
et al., 1985; Kendall, 1981; Von Gaudecker and Schmale,
1974; Von Gaudecker, 1986) or represent regions where
unwanted antigens are accumulated (Kendall, 1981).
ULTRASTRUCTURAL HETEROGENEITY
Cortical Epithelium
Recently, we have described four ultrastructurally
identified EC subtypes in the cortex of the rat thymus
and provided semiquantitative data on their tissue
distribution (De Waal et al., 1993a,b). The morphological designation of EC subtypes was performed using the
characteristics given in Table 1, the nuclear and cytoplasmic electron-density being the main parameters.
The EC.1 subtype (Fig. 1a) is defined on its location in
the subcapsular tissue. Within the EC.1 population,
there is a heterogeneity of ‘‘pale,’’ ‘‘intermediate,’’ and
‘‘dark’’ cells, the intermediate manifestation being the
most frequently occurring one. Such manifestations
resemble either the pale EC.2 (Fig. 1b), intermediate
EC.3 (Fig. 1c), or dark EC.4 (Fig. 1d). As the intermediate EC.3 cells (Fig. 1c) comprise a spectrum of cells
ranging from relatively electron-lucent to electrondense, two additional parameters were used to distinguish these cells from pale EC.2 (Fig. 1b) and dark EC.4
(Fig. 1d). The round shape of the nucleus was a
parameter to read pale cells on the one hand, and the
irregularly shaped nucleus was used as a parameter to
judge cells as intermediate and dark. Secondly, dark
cells were separated from intermediate ones on the
basis of the presence of an electron-dense ground
substance. In the rat thymic cortex, the pale EC.2 was
the most frequently occurring EC subtype comprising
about 60% of the total EC number. Intermediate EC.3
were occasionally seen (about 25%), whereas dark EC.4
occurred in very low numbers only (about 5% of the
total EC number). Due to the amorphous cytoplasmic
ground substance, in these cells tonofilaments were
sometimes hard to distinguish. Cytoplasmic vacuoles,
however, could easily be recognized as a result of their
clear appearance. As classical secretory granules are
very rare in the thymic epithelium, such clear cytoplasmic vacuoles occurring in all EC subtypes are thought
to be the terminal element of the secretory apparatus
(Nabarra and Andrianarison, 1987b). These cytoplasmic vacuoles show a typical ultrastructural morphology: an electron-lucent matrix containing coarsely
granular electron-dense material, often adhering to the
inner face of the vacuolar membrane (Duijvestijn and
Hoefsmit, 1981; Nabarra and Andrianarison, 1987a).
All cortical EC subtypes were interconnected by desmosomes. Mostly mononucleate EC were seen, but binucleate pale EC.2 were observed in low frequency as well.
Medullary Epithelium
We have described the ultrastructural features of the
medullary epithelium in the rat thymus as well (De
Waal et al., 1996). The morphological designation of
medullary EC subtypes (EC.1 to EC.6) was performed
using the characteristics given in Table 2. EC.1 (Fig.
2a), EC.2 (Fig. 2b), EC.3 (Fig. 2c), and EC.4 (Fig. 2d) do
not differ from analogous EC subtypes in the cortex.
Their relative frequencies of occurrence are about 3%
(EC.1), 36% (EC.2), 54% (EC.3), and 1% (EC.4), respectively. EC.5 (Fig. 2e) represents an undifferentiated EC
subtype, which comprises only 1% of the total medullary EC population. In the medulla of the human
229
THYMIC EPITHELIAL CELL HETEROGENEITY
TABLE 1. Main ultrastructural features of cortical epithelial cell (EC) subtypes in the rat thymus
Subtype
Designation
Ultrastructural morphology
Location
EC.1
Subcapsular
Continuous layer of cells bordering the thymic tissue
beneath the capsule
EC.2
Pale
EC.3
Intermediate
EC.4
Dark
Low to high nuclear and cytoplasmic electron-density; heteroor euchromatic nucleus; prominent tonofilaments; rather
well-developed Golgi complexes and RER; regularly electron-lucent cytoplasmic vacuoles
Low nuclear and cytoplasmic electron-density; round, euchromatic nucleus; rather well-developed Golgi complexes and
RER; inconspicuous tonofilaments; electron-lucent cytoplasmic vacuoles
Moderate nuclear and cytoplasmic electron-density; euchromatic or heterochromatic nucleus of irregular shape; inconspicuous Golgi complex and tonofilaments; electron-lucent
cytoplasmic vacuoles
High nuclear and cytoplasmic electron-density; irregularly
shaped, heterochromatic nucleus; electron-lucent cytoplasmic vacuoles; inconspicuous tonofilaments
thymus, EC.5 are usually arranged in small groups
(Van De Wijngaert et al., 1984), but in the rat thymic
medulla they occur as solitary cells. The EC.6 subtype
in the human thymus represents a large medullary EC
with an electron-lucent cytoplasm, a round to oval
euchromatic nucleus, prominent tonofilaments, welldeveloped rough endoplasmic reticulum, and small
secretory vesicles (Van De Wijngaert et al., 1984). In the
human thymic medulla, EC.4 and EC.6 are found in or
around Hassall’s corpuscles (Van De Wijngaert et al.,
1984). In the rat strain used in our studies, which lacks
Hassall’s corpuscles in the thymic medulla, EC displaying a similar ultrastructure as the human EC.6 subtype
were not present. However, large EC with low to
moderate nuclear and cytoplasmic electron-density were
seen (comprising 4% of the total population of medullary EC) either solitarily or in small groups, which
showed a prominent cluster of large, electron-lucent
cytoplasmic vacuoles, often carrying microvilli projecting into the vacuolar lumen. These vacuoles may contain flocculent material. In the rat classification, these
cells were designated EC.6 (Fig. 2f).
The first ultrastructural description of dark cells in
the mouse thymus (and lymph nodes) was published by
Izard and De Harven in 1968. These authors claimed
that these so-called ‘‘dense reticular cells’’ were not part
of the EC population. They however suggested a close
relationship between ‘‘dark reticular cells’’ and EC,
based upon the observation of many intermediate forms
of variable size and density. More than a decade later,
ultrastructural studies have confirmed the presence of
pale and dark EC with reference to their nuclear and
cytoplasmic electron density (Kendall, 1981; Singh,
1981). From an evolutionary point of view, differences
in electron-density seem to be well conserved in the
thymic epithelium as judged from observations in the
thymus of the rainbow trout (Castillo et al., 1991) and
the axolotl thymus (Tournefier et al., 1990). In the
human thymus, six EC subpopulations have been described based on ultrastructural characteristics (Van
De Wijngaert et al., 1984). This classification has been
confirmed by other investigators for the human, mouse,
and rat thymus (Boyd et al., 1993; Clarke and Kendall,
1989; Kendall, 1986, 1988, 1991; Kendall et al., 1988;
Von Gaudecker, 1991). This (similar) heterogeneity has
been claimed to hold for all vertebrate thymuses (Kendall, 1991). Our classification for the rat thymus indeed
Scattered in the cortex, predominant in the outer
cortex
Scattered in the cortex, predominant in the mid and
deep cortex
Mid and deep cortex, predominant in the deep cortex
closely resembles that of Van De Wijngaert and coworkers (1984) for the human situation. They designated
four EC subtypes in the cortex and medulla of the
human thymus. The first subtype is called EC.1, representing the subcapsular (cortex) and perivascular EC
(medulla). The other three subtypes are defined by
increasing grades of electron-density (i.e., pale EC.2,
intermediate EC.3, and dark EC.4). As in the rat, a
comparable heterogeneity (pale to dark forms) within
the EC.1 population was present in the human thymus.
Two further subtypes are exclusively found in the
medulla: EC.5 showing the ultrastructural characteristics of undifferentiated elements, and EC.6 displaying
signs of high metabolic activity (Van De Wijngaert et
al., 1984). The cortical pale EC.2, intermediate EC.3,
and dark EC.4 show a gradation in representation from
the outer subcapsule to the inner cortex (Boyd et al.,
1993; Van De Wijngaert et al., 1984). In the human
thymus, pale EC.2 and intermediate EC.3 in the cortex
probably contribute to TNC (Boyd et al., 1993; Kendall,
1991; Van De Wijngaert et al., 1984; Von Gaudecker,
1991). In contrast to the human thymus (Van De
Wijngaert et al., 1984), the ultrastructural features of
EC.2, EC.3, and EC.4 in the cortex of the rat thymus
are slightly different from those characterizing their
medullary counterparts (Tables 1, 2). In particular,
tonofilaments are more prominent in medullary EC.2
and EC.3 than they are in cortical EC.2 and EC.3. Also,
EC.6 in the medulla of the rat thymus has a completely
different ultrastructure in comparison with the human
situation. These cells have been designated as ‘‘cystic’’
(Mandel, 1970), ‘‘hypertrophic’’ (Bennett, 1978), or ‘‘alveolar layrinthine’’ EC (Nabarra and Andrianarison,
1987b). Probably, this EC subtype is involved in thymic
hormone production (Bennett, 1978; Mandel, 1970).
IMMUNOHISTOCHEMICAL HETEROGENEITY
To elucidate the structural organization of the thymic
epithelium, many immunohistochemical and immunoelectron microscopic studies have been conducted (for
references see Boyd et al., 1993). Extensive panels of
monoclonal antibodies have revealed complex distribution patterns of keratin subtypes typical of simple and
stratified epithelia (Colic et al., 1988a, 1989; Farr and
Braddy, 1989; Gay-Bellile et al., 1986; Laster et al.,
1986; Nicolas et al., 1985, 1989; Savino and Dardenne,
1988; Von Gaudecker et al., 1986). Immunostaining
230
E.J. DE WAAL AND L.H.P.M. RADEMAKERS
Fig. 1. Electron micrographs of the various cortical epithelial cell subtypes. a: EC1. Subcapsular epithelial cell (EC) showing prominent
tonofilaments (arrows). Asterisk: Capsular connective tissue; arrowhead: Golgi complex; double arrow: basement membrane. 38,200. Inset:
Detail of a cluster of electron-lucent vacuoles containing vesicular structures which are regularly observed in subcapsular EC. 314,000. b: EC2.
Pale EC having an extensive cytoplasm containing numerous polyribosomes. Desmosomes (arrows) are regularly present. Arrowhead: Golgi
complex. 35,200. c: EC3. Intermediate EC (asterisk) having a heterochromatic nucleus and a low amount of cytoplasm. Arrows: lysosomes;
arrowhead: cytoplasmic vacuole. 39,500. d: EC4. Dark EC with cytoplasmic vacuoles (arrow) and dilated cisterns of the rough endoplasmic
reticulum (arrowheads). Large arrow: bundle of tonofilaments. 37,200.
THYMIC EPITHELIAL CELL HETEROGENEITY
TABLE 2. Main ultrastructural features of medullary epithelial cell
(EC) subtypes in the rat thymus
Subtype
Designation
EC.1
Perivascular
EC.2
Pale
EC.3
Intermediate
EC.4
Dark
EC.5
Undifferentiated
EC.6
Cystic
Ultrastructural characteristics
Located around capillaries; low to high
nuclear and cytoplasmic electrondensity; nucleus round or irregularly
shaped, hetero- or euchromatic;
prominent tonofilaments; electronlucent cytoplasmic vacuoles
Low nuclear and cytoplasmic electrondensity; round, euchromatic nucleus;
poorly to moderately developed tonofilaments; electron-lucent cytoplasmic vacuoles
Moderate nuclear and cytoplasmic electron-density; irregularly shaped
nucleus, hetero- or euchromatic;
inconcpicuous, moderately developed
tonofilaments; electron-lucent cytoplasmic vacuoles
High nuclear and cytoplasmic electrondensity; nucleus of irregular shape,
hetero-chromatic; inconspicuous
tonofilaments; few cytoplasmic vacuoles
Low nuclear and cytoplasmic electrondensity; round, euchromatic nucleus;
inconspicuous tonofilaments; polyribosomes
Low to moderate nuclear and cytoplasmic electron-density; eccentric,
round or irregularly shaped heteroor euchromatic nucleus; rather welldeveloped rough endoplasmatic reticulum; small tonofilaments; large
intra-cytoplasmic cysts with intraluminal microvilli
with anti-keratin antibodies has revealed a different
topography of labeled EC in rat, mouse, and human
thymus (Meireles De Souza et al., 1993). This group
observed an important similarity in the topography of
specific keratin subclasses in species of the same mammalian order. Other antigenic determinants with an
unknown functional significance demonstrated complex staining patterns as well (Boyd et al., 1993; Colic et
al., 1988b; De Maagd et al., 1985; Izon and Boyd, 1990;
Kampinga et al., 1987, 1989; Kaneshima et al., 1987;
McFarland et al., 1984; Rouse et al., 1988; Von Gaudecker et al., 1986, 1989). Yet, four broad classes of
epithelium have been identified phenotypically: subcapsule/perivascular, cortical, medullary EC, and medullary EC forming Hassall’s corpuscles (Boyd et al., 1993;
Janossy et al., 1986; Kampinga et al., 1989; McFarland
et al., 1984; Van Ewijk, 1991). Many monoclonal antibodies raised against thymic EC react either with subcapsular and medullary epithelium on the one hand or
with cortical epithelium on the other hand (Boyd et al.,
1993; Colic et al., 1988b; Farr et al., 1991; Haynes et al.,
1983, 1984; Izon and Boyd, 1990; Kampinga et al.,
1987; Kaneshima et al., 1987; Lampert and Ritter,
1988; Pavlovic et al., 1993; Von Gaudecker, 1991). Some
antibodies to EC detect epitopes that are also present
on thymocytes (Godfrey et al., 1990) or IDC (Izon et al.,
1994). Based on distribution patterns of keratin expression in the hamster thymus, it has been suggested that
phenotypic markers of EC heterogeneity should be
considered as indicators of a continuous plasticity of the
231
epithelium, rather than determinants to define definitive EC subsets (Lannes Vieira et al., 1994; Meireles De
Souza and Savino, 1993).
The subcapsular and medullary epithelium constitute the endocrine component of the thymus (Auger et
al., 1987; Geenen et al., 1992; Von Gaudecker et al.,
1986; Von Gaudecker, 1991), although, in the mouse
and human thymus, thymic hormones have been localized in cortical EC as well (Auger et al., 1984; Jambon
et al., 1981; Savino and Dardenne, 1984; Schuurman et
al., 1985). Neuroendocrine markers are also preferentially distributed in the subcapsular and medullary
epithelium of the human thymus. Scattered in the
cortex, solitary EC express such markers as well
(Geenen et al., 1987; Moll et al., 1988).
Whereas all EC express MHC class I products, MHC
class II antigens are differentially expressed in the
cortical and medullary epithelium. Cortical EC are
strongly MHC class II-positive in mice (Farr and Nakane, 1983; Farr and Sidman, 1984; Nabarra and
Papiernik, 1988; Rouse et al., 1979; Van Ewijk et al.,
1980), rats (Kendall et al., 1990) and humans (Hamblin
and Edgeworth, 1988; Ritter et al., 1981; Van Baarlen
et al., 1989; Von Gaudecker et al., 1986). The extent of
MHC class II immunolabeling in the medullary epithelium varies between different species (Ritter and Crispe,
1992). In mice, a large proportion of the medullary EC
expresses MHC class II molecules (Farr et al., 1993;
Farr and Nakane, 1983; Nabarra and Papiernik, 1988;
Rouse et al., 1979; Surh et al., 1992; Van Ewijk, 1991;
Van Ewijk et al., 1980; Van Ewijk, 1984). In contrast,
MHC class II immunolabeling is far less prominent or
even absent in the medullary epithelium of the rat
(Kendall et al., 1990; Schuurman et al., 1990) and
human thymus (Hamblin and Edgeworth, 1988; Haynes,
1984; Van Baarlen et al., 1989; Von Gaudecker et al.,
1986; Von Gaudecker et al., 1997). The subcapsular
epithelium may express MHC class II antigens in mice
(Farr et al., 1992) and humans (Haynes, 1984; Janossy
et al., 1986; McFarland et al., 1984).
CONCLUDING REMARKS
Early light microscopic studies in mice (Cordier and
Haumont, 1980) have suggested that cortical EC are
ectodermal and subcapsular/medullary EC endodermal
in origin. Early studies suggested that subcapsular/
perivascular and pale EC in the cortex and medulla of
the human thymus are descendants of the ectoderm,
whereas intermediate and dark EC in the medulla and
inner cortex come from the endoderm (Norris, 1938;
Von Gaudecker, 1986). Recent immunohistological studies, however, have questioned the dual origin of the
thymic epithelium, suggesting that there is a single
epithelial stem cell that can give rise to the many
different EC subpopulations during thymic development (Boyd et al., 1993; Lampert and Ritter, 1988;
Kendall, 1991; Ritter and Boyd, 1993; Von Gaudecker,
1991). This hypothesis is supported by the presence of
EC having antigenic characteristics of both cortical and
subcapsular/medullary epithelium in the involuted thymus of young children after a period of acute illness
(Van Baarlen et al., 1989), some thymomas (Lampert
and Ritter, 1988; Willcox et al., 1987) and cultured
thymic fragments implanted in athymic (nude) rats
(Kendall et al., 1988). Early ultrastructural observa-
232
E.J. DE WAAL AND L.H.P.M. RADEMAKERS
Fig. 2. Electron micrographs of medullary epithelial cell subtypes. a: EC1. Perivascular EC with elongated cytoplasmic extensions bordering
connective tissue (asterisk) surrounding a capillary. Desmosomes (arrows) are well developed. Arrowhead: basement lamina of EC. 39,200. b:
EC2. Pale EC with voluminous cytoplasm having a high density of polyribosomes. Golgi complex and RER are well developed. Vacuoles with
amorphous content (arrows). 37,000. c: EC3. Intermediate EC with moderate cytoplasmic and nuclear electron density. Tonofilaments in
connection with well-developed desmosomes are present (arrows). 35,800. d: EC4. Dark EC having an extremely dilated RER and cytoplasmic
vacuoles. 36,200. e: EC5. Undifferentiated EC containing a high density of polyribosomes and distinct tonofilaments (arrows). 39,000. f: EC6.
Cystic EC having well-developed rough endoplasmic reticulum. Note a cluster of intracytoplasmic cysts (arrowhead). Some intraluminal
microvilli are present (arrow). 35,400.
THYMIC EPITHELIAL CELL HETEROGENEITY
Fig. 2.
tions in the rat thymus have suggested the possible
existence of one lineage of EC as well (Hwang et al.,
1974). This issue will be further discussed by Von
Gaudecker and coworkers, and by Röpke et al. (this
issue).
Immunohistochemical studies have provided a basis
to postulate that thymic EC differentiate through phenotypically discrete stages in vivo (Nicolas et al., 1989).
Early ultrastructural observations on the mouse thymus have suggested a sequential differentiation of EC
as well (Mandel, 1970). In this hypothesis, medullary
EC ultimately form Hassall’s bodies by terminal differentiation (Laster et al., 1986; Lobach et al., 1985, 1987;
Nicolas et al., 1989). Human Hassall’s corpuscles reveal
a striking similarity to keratinizing squamous epithelium in the epidermis (Laster et al., 1986; Von Gaudecker and Schmale, 1974). Similarities between the
thymic medulla and the epidermis have been postulated based on antigenic cross-reactivities as well
(Schmitt et al., 1987). From patterns of keratin distribution within the human thymus, Laster and coworkers
(1986) suggested that thymic EC undergo a pathway of
differentiation similar to that observed in epidermal
keratinocytes. Based on the ultrastructure of the human thymic epithelium, Van De Wijngaert and coworkers (1984) likewise have postulated that morphologically distinct EC subtypes represent sequential stages
in a differentiation process. Our recent ultrastructural
studies on alterations of the rat thymic epithelium after
chemical exposure suggest a similar phenomenon (De
Waal et al., 1993b).
233
(Continued.)
ACKNOWLEDGMENTS
Henk-Jan Schuurman (Sandoz Pharma Ltd, Basel,
Switzerland), Henk van Loveren and Joseph G. Vos
(National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands) participated in some studies on the rat thymic epithelium
upon which this review is based. Thanks are due to Dr.
R.A. de Weger (Department of Pathology, Academic
Hospital Utrecht) for reviewing the final manuscript.
Mr. M. Niekerk and Mr. R. Scriwanek are acknowledged for their excellent photographic assistance.
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