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Extrahepatic and Intrahepatic Human Portal Interstitial Cajal Cells.

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THE ANATOMICAL RECORD 294:1382–1392 (2011)
Extrahepatic and Intrahepatic Human
Portal Interstitial Cajal Cells
Discipline of Anatomy, Faculty of Dental Medicine, ‘‘Carol Davila’’ University of Medicine
and Pharmacy, Bucharest, Romania
Department of Plant and Animal Cytobiology, Institute of Biology – Romanian Academy,
Bucharest, Romania
Discipline of Pathologic Anatomy, Faculty of Medicine, ‘‘Carol Davila’’ University of
Medicine and Pharmacy, Bucharest, Romania
‘‘Mina Minovici’’ National Institute of Legal Medicine, Bucharest, Romania
Faculty of Medicine, ‘‘Carol Davila’’ University of Medicine and Pharmacy,
Bucharest, Romania
Discipline of Infectious Diseases, Faculty of Medicine,
‘‘Carol Davila’’ University of Medicine and Pharmacy, Bucharest, Romania
‘‘Prof. Dr. Matei Bals
’’ National Institute for Infectious Diseases, Bucharest, Romania
Portal interstitial cells of Cajal (PICCs), acting as vascular pacemakers,
were previously only identified in nonhumans. Moreover, there is no evidence
available about the presence of such cells within the liver. The objective of the
study is to evaluate whether or not PICCs are identifiable in humans and, if
they are, whether or not they are following the scaffold of portal vein (PV)
branches within the liver. We obtained extrahepatic PVs and liver samples from
six adult human cadavers, negative for liver disease, in accordance with ethical
rules. They were stained with hematoxylin-eosin (HE) and Giemsa, and then
we performed immunohistochemistry on formalin-fixed paraffin-embedded
specimens for CD117/c-kit, a marker of the Cajal’s cells. Immune labeling was
also performed for S-100 protein, desmin, glial fibrillary acidic protein (GFAP),
neurofilaments, a-smooth muscle actin (a-SMA), and CD34. c-kit-Positive
PICCs were identified within the extrahepatic PV, in portal spaces, and septa.
On adjacent sections, these PICCs were negative for all the other antibodies
used. In conclusion, our study confirms the presence of extrahepatic PICCs on
humans, which may act as a possible intrinsic pacemaker in the human PV.
However, the intrahepatic PICCs, which were evidenced here for the first time,
are in need for further experimental studies to evaluate their functional role. A
promising further direction of the study is the PICCs role in the idiopathic porC 2011 Wiley-Liss, Inc.
tal hypertension. Anat Rec, 294:1382–1392, 2011. V
Key words: liver; CD117/c-kit;
Abbreviations used: DC ¼ dendritic cell; GFAP ¼ glial
fibrillary acidic protein; GI ¼ gastrointestinal; HE ¼
hematoxylin-eosin; HSC ¼ hepatic stellate cell; IA ¼ inner
adventitia of the portal vein, between the longitudinal muscle
bundles (LMBs) and the media; IC ¼ interstitial cell; ICC ¼
interstitial cells of Cajal; ICLC ¼ interstitial Cajal-like cell; OA
¼ outer adventitia of the portal vein, covering the LMBs; PICC
¼ portal interstitial cells of Cajal; PV ¼ portal vein; PVb ¼
intrahepatic portal vein branch; RPV ¼ rabbit portal vein; SMA
¼ -smooth muscle actin; SMC ¼ smooth muscle cell.
Grant sponsors: European Social Fund and the Romanian
Government [the Sectoral Operational Programme Human
Resources Development (SOP HRD)]; Grant number: POSDRU/
*Correspondence to: M.C. Rusu, MD, PhD (Med.), PhD stud.
(Biol.), ‘‘Carol Davila’’ University of Medicine and Pharmacy, 8
Eroilor Sanitari Blvd., Bucharest RO-76241, Romania. E-mail:
Received 13 November 2010; Accepted 16 May 2011
DOI 10.1002/ar.21441
Published online 28 June 2011 in Wiley Online Library
TABLE 1. Antibodies used for the study of the PICCs
Clonality, clone
Source, code
External positive
Monoclonal, Y145
S100 Protein cocktail
IgG1 þ IgG2a
Glial fibrillary acidic
protein (GFAP{P})
Smooth muscle
actin (SMA)
Monoclonal, QBEnd/10
15E2E2 þ 4C4.9
Monoclonal, D33
Polyclonal, N/A
Skin (mast cells),
testis (germ cells)
Tonsil, skin
Monoclonal, C04018
IgG1 kappa
Monoclonal, NE14
BioGenex, AM073-10M
blood vessels
Fig. 1. Giemsa stain. Multipolar cell (arrow), with moniliform processes (arrowheads), closely related to a longitudinal muscle bundle of
the extrahepatic PV wall.
Interstitial cells of Cajal (ICCs), first described more
than 100 years ago and initially thought to be present
only in the gastrointestinal tract, are now considered to
be responsible for the generation and/or propagation of
slow waves (Povstyan et al., 2003; Huang and Xu, 2010).
It is now known that ICCs play important roles in the
regulation of gastrointestinal motility.
ICCs outside the gastrointestinal tract are usually
known as interstitial Cajal-like cells (ICLCs). More
recently, ICLCs with long and moniliform processes were
termed telocytes and the respective processes were
named telopodes (Popescu and Faussone-Pellegrini,
ICCs are known to be immunopositive for c-kit, a
proto-oncogene that encodes a tyrosine kinase receptor
(Mei et al., 2009), making it a useful marker for these
cells (Ward and Sanders, 2001; Povstyan et al., 2003;
Harhun et al., 2005; Sanders et al., 2006; Popescu and
Faussone-Pellegrini, 2010). However, it is not mandatory
for all ICCs to be labeled with c-kit antibodies (Huizinga
and Faussone-Pellegrini, 2005). ICCs from the small
intestine are divided in two subgroups, one located
within the myenteric plexus (ICC-MY), with a pacemaker function and another closely associated with the
deep muscular plexus (ICC-DMP), playing a role in the
mediation of neural inputs (Mei et al., 2009; Huang and
Xu, 2010). These two subgroups of ICCs are known as ckit positive (Chen et al., 2007).
c-kit positive ICCs were for the first time identified in
the wall of the portal vein (PV) in rabbits by Povstyan
et al. (2003); further studies found that these portal interstitial cells of Cajal (PICCs) may act as pacemakers,
controlling rhythmical contractions of the PV (Harhun
et al., 2004).
Like ICCs but unlike smooth muscle cells, ICLCs are
positively stained with methylene blue (Formey et al.,
2011). ICLCs were detected in the myocardial sleeves of
the human pulmonary veins (Gherghiceanu et al., 2008;
Morel et al., 2008), especially in patients with atrial fibrillation, and were presumed to act as pacemaker cells
in these veins (Morel et al., 2008).
No studies were yet performed to check the presence
of PICCs in humans, and no presence of the portal hepatic ICCs was identified, even though it is known that
the ICLCs are present in rhythmically active structures
(Huizinga et al., 2009) such as the heart (Hinescu and
Popescu, 2005; Hinescu et al., 2006; Popescu et al.,
2006), PV (Harhun et al., 2004), the upper urinary tract
and the urinary bladder (Lang et al., 2006), and the gallbladder (Hinescu et al., 2007).
Our objectives for this study were (1) to evaluate the
presence of PICCs in humans and (2) to check whether
or not they follow the portal venous scaffold within the
liver. The study was designed as a qualitative one.
PV tissue samples were obtained from six human
adult cadavers, negative for any liver disease, (aged 58–
72 years, male:female ratio 2:1), from the following topographic locations: retropancreatic, retroduodenal, and
intraomental. Liver samples were also taken.
The study was performed according to the national
laws regarding human cadaver manipulation, medical
legal practice, and the reform of medical system, and
Council of Europe, Committee of Ministers, Recommendation No. R (99) 3 on the Harmonization of MedicoLegal Autopsy Rules. The investigation was in
agreement with the principles outlined in the Declaration of Helsinki. The Institutional Ethics Committee
granted the approval.
The samples were embedded in paraffin, sectioned at
3 lm, and stained with hematoxylin-eosin (HE) and
Fig. 2. Oblique cut through the retroduodenal portal vein; positive CD117 immunolabeling (arrows) of
cells in the vicinity of longitudinal muscle bundles (LMBs). The portal inner adventitia (IA) and media (M)
are identified.
Fig. 3. PICC (arrow) of the extrahepatic PV, closely related to a longitudinal muscle bundle (lmb), and sending off moniliform processes
Giemsa stain, which is a mixture of methylene blue, eosin, and azure B. Histologically, the samples were negative for liver diseases. Immunohistochemistry on
formalin-fixed paraffin-embedded tissues was performed,
and adjacent sections were labeled with antibodies for
CD117/c-kit, CD34, S-100 protein, desmin, glial fibrillary
acidic protein (GFAP), a-smooth muscle actin (a-SMA),
Fig. 4. PICC (arrow) of the extrahepatic PV, closely related to a circular muscle bundle (cmb), and sending off a moniliform process
and neurofilaments (Table 1) using the ABC method.
External positive controls were specifically labeled (see
Table 1) and sections treated without primary antibodies
served as negative controls.
Microscopic slides were analyzed and snapshots were
taken and scaled by using a ZEISS working station consisting of an AxioImager M1 microscope with an
Fig. 5. Immune labeling on successive sections for c-kit, desmin, and CD34. Within the wall of the extrahepatic portal vein c-kit positive cells (arrows) are desmin- and CD34-negative. However, adjacent c-kit
negative cells are either desmin- and CD34-negative (arrowhead) or desmin-positive and CD34-negative (*).
AxioCam HRc camera and the digital image processing
software AxioVision.
Histological Evaluation of the Portal Vein
PVs, distinctively identified on slides, consisted of a
distinct intima, a narrow tunica media mainly composed
of circular smooth muscle fibers and a thick adventitia,
the later embedding longitudinal bundles of smooth
muscle cells between two sublayers of collagenic extracellular matrix, which we have termed inner adventitia
(IA), one between the longitudinal muscle and the media
and outer adventitia (OA), the sublayer covering the longitudinal bundles of smooth muscle cells.
Giemsa stain distinctively identified dark blue multipolar cells with moniliform processes (Fig. 1) closely
related to muscle bundles of the extrahepatic PVs. These
were clearly differentiated from mast cells, which lack
processes and are usually present in perivascular
PICCs of the Extrahepatic PV
Within PV walls, CD117/c-kit–positive cells (Figs. 2–8)
were identified at all topographic levels (retropancreatic,
retroduodenal, and intraomental). Within the PV wall,
these cells were topographically located either within
the IA, or the OA and were, closely but not exclusively,
apposed to the smooth muscular bundles, both longitudinal (Figs. 2 and 3) and circular (Fig. 4).
These cells were considered as PICCs, and were further immunolabeled for CD34, desmin, GFAP, neurofilaments, a-SMA, and S100 protein (Figs. 5–8). As it
resulted from immune labeling of the adjacent sections
(labeling on successive slides), the c-kit positive PICCS
• CD34 negative (Figs. 5–7);
• desmin negative (Figs. 5 and 7);
• GFAP negative;
• neurofilaments negative;
Fig. 6. Immune labeling on successive sections for c-kit and CD34.
c-kit-Positive cells with moniliform processes (arrows) are CD34-negative. Adjacent c-kit-negative cells (arrowhead) are CD34-positive.
• -SMA negative (Fig. 8);
• S100 protein negative (Fig. 7).
These PICCs appeared as multipolar, either polygonal
or rounded/oval-shaped cells, with numerous processes
(Figs. 2–8), often moniliform (Figs. 3, 4, 6, 7).
CD34 immunolabeling found portal IA and OA to
contain immunopositive cells scaffolding two wellrepresented mesenchymal layers within those adventitial sublayers.
Intrahepatic PICCs
We have also identified CD117/c-kit–positive cells
within the hepatic tissue, distinctively located at the
level of the portal spaces and septa (Figs. 9–14):
Fig. 7. Immune labeling on successive sections for c-kit (A), S100 protein (B), CD34 (C), and desmin
(D). Two c-kit-positive cells with moniliform processes (arrow, arrowhead) are S-100-negative (A, B). A
neighbor cell (*), c-kit negative, is CD34- and desmin-positive (A, C, and D).
Fig. 8. Immune labeling on successive sections for c-kit (right panel), and a-smooth muscle actin
(SMA, left panel). A c-kit-positive cell (arrow) is SMA-negative.
Fig. 9. Hepatic portal space with CD117/c-kit positive cells on the portal side of the limiting plate
(arrowheads), within the portal space (thin arrows) and in the periphery of the lobules (thick arrowheads).
Fig. 10. Peribiliary c-kit positive cells (arrows) of the portal space. One of these is magnified (*, inset).
BD, bile duct; PVb, portal vein branch.
Fig. 11. c-kit positive cells (arrows) are identified within the portal septa but not close to a terminal
vein (TV).
Fig. 12. c-kit positive ICLCs on the portal side of the limiting plate. Scalebar corresponds to all panels.
1. at the level of the lobular limiting plate, on its portal
side (Fig. 9);
2. within the portal spaces/septa (Figs. 9 and 11), there
were also ICCs concentrated around the bile ducts at
that level (Fig. 10) but we found no c-kit positive cells
neighboring terminal veins (Fig. 11);
3. in the periphery of the hepatic lobules (Fig. 9).
Morphologically, the intrahepatic PICCs were single or
grouped multipolar cells, having processes with even or
uneven calibers (moniliform processes) (Figs. 10, 12, 13).
The morphological pattern was similar for the PICCs of
the limiting plate (Fig. 12) and those of the portal spaces
and septa (Fig. 13). The PICCs were equally distributed
near arteries, PV branches, nerves, and bile ducts within
the portal spaces. We have also identified a uniform circumferential distribution of the PICCS around the bile
ducts of the portal spaces (Fig. 10).
CD34 immunolabeling (Fig. 14) identified the positive
cells mainly located on the portal side of the limiting
plate. However, on successive sections, immune labeling
for CD34 and CD117 was not concordant and CD34-positive cells were not identified within the periphery of the
hepatic lobules.
Finally, the intrahepatic PICCs had a similar immune
labeling pattern as the extrahepatic ones—negative for
CD34, S100 protein, desmin, GFAP (Fig. 15), and
Fig. 13. c-kit positive ICLCs of the portal spaces. Scalebars: 20 lm.
The wall of the portal vein in rabbit (RPV) is structurally comparable to human PV (Harhun et al.,
2005). The RPV is a spontaneously active blood vessel
(Bolton et al., 2004) and the distribution of the PICCs
in the wall of the RPV resembles the distribution of
ICCs in the gastrointestinal (GI) tract (Harhun et al.,
Therefore, for the first time, we bring a proof of the
presence of the portal ICCs in humans and the first evidence for the intrahepatic ICCs located within the portal
spaces and septa, and in the periphery of the hepatic
lobules. These PICCs have the morphological feature
that allows their definition as portal telocytes, the moniliform telopodes. Therefore, our results bridge the interspecies gap, further allowing a better extrapolation of
the experimental results in humans.
Giemsa stains previously identified ICLCs in the
mammary gland stroma (Radu et al., 2005) and the fallopian tube (Popescu et al., 2005a). According to our findings, this stain is also reliable in identifying the PICCs/
portal telocytes, before any immunohistochemical
Most ICCs belong to a spectrum, ranging from cell
types very similar to SMCs (‘‘myoid cells’’) to cell types
with ultrastructural features, hardly distinguishable
from classic descriptions of fibroblasts (fibroblast-like or
fibroid cells) (Rumessen and Vanderwinden, 2003).
Regarding the PICCs we have identified, both the extrahepatic and the intrahepatic PICCs were aSMA-negative, the myoid phenotype of these PICCs being
It must be taken into account that c-kit may be also
considered a marker of primitive, pluripotent cell types,
Fig. 14. CD34-positive cells (arrows) on the portal side of the limiting plate; on successive sections,
these are different to the c-kit positive cells located on the portal side of the limiting plate.
Fig. 15. No positive immune labeling for GFAP is evident at the
level of the portal spaces. PVb, portal vein branch; BD, bile duct; a,
as it was previously documented that CD34-positive
stem cells in bone marrow express c-kit (Hibbert et al.,
2004). CD34 monoclonal antibodies are known to label
endothelial cells, mesenchymal cells and stroma fibro-
cytes functioning as matrix-producing cells (Leong et al.,
2003; Pusztaszeri et al., 2006). However, as the c-kit
cells we have identified were CD34-negative on adjacent
sections, we excluded this possibility.
The concept of a diffuse stellate cell system in mammals was suggested (Zhao and Burt, 2007). However, hepatic stellate cells (HSCs) are mesenchymal cells,
usually GFAP- and/or desmin-positive (Yokoi et al., 1984;
Gard et al., 1985; Buniatian et al., 1996; Zhao and Burt,
2007) and were not proven to be c-kit-positive. Therefore, we have a positive differential diagnosis between
our PICCs, desmin-, and GFAP-negative, and the HSCs.
Moreover, the presence of long and ‘‘moniliform’’ cytoplasmic processes makes a clear difference between
ICCs/ICLCs and resting stellate cells (Popescu et al.,
Dendritic cells (DCs) are known as the most potent
professional antigen-presenting cells (Gulubova et al.,
2008). DCs may be labeled nonspecifically with c-kit
(Chen et al., 2007) but are specifically labeled with S100 protein (Gulubova et al., 2008). Regarding the
PICCs we evaluated, there were c-kit-positive and S-100negative, so the diagnostic of DCs was excluded.
In our study, extrahepatic PICCs were identified close
to the circular and longitudinal portal muscle bundles.
These vicinities could qualify the extrahepatic PICCs as
possible generators of spontaneous rhythmical local
waves, as it was demonstrated for the RPV (Harhun
et al., 2005), but this is only speculative at this time and
further studies need to be conducted to determine the
exact role(s) of the extrahepatic PICCs in humans.
PICCs appeared mostly, but not exclusively, as constituents of the portal stroma, within the liver, at which
level the portal venous branches lack muscular layers.
As hepatic PICCs were identified on both sides of the
lobular limiting plate, a role at this interface may be
presumed, and this led us to strongly suppose that these
hepatic PICCs can be involved in the mediation of the
neural transmission, before portal pacemaking. Nevertheless, a pacemaking function of the hepatic PICCs cannot be ignored as we identified such cells near arteries,
nerves, and biliary tracts. Therefore, the intrahepatic
PICCs could equally qualify as arterial ICLCs, perineural, or biliary ICLCs, as it was proven in various studies
(Daniel, 2001; Lavoie et al., 2007; Ahmadi et al., 2010;
Pucovsky, 2010).
The PICCs we identified are ICLCs, as they are ICCs
located outside the gastrointestinal tract. Moreover, as
these cells have moniliform processes, they could be labeled as telocytes, the only morphological difference
between ICLCs and telocytes being the presence of moniliform telopodes (Faussone-Pellegrini and Bani, 2010;
Popescu and Faussone-Pellegrini, 2010).
The switch from an ICC to a SMC phenotype was considered an extremely important phenomenon that might
be used for therapeutic purposes when ICC number is
decreased in human GI motility disorders (Sanders
et al., 2000); such phenotypic switch must be evaluated
on larger samples of human PV to evaluate whether or
not therapeutic approaches may be considered in PV
A promising direction of research may be if and how
these PICCs are involved in the idiopathic portal hypertension (Okudaira et al., 2002; Kitao et al., 2009), when
it is possible that a portal venous blood insufficiency to
be responsible for hepatic parenchymal damage (Tsuneyama et al., 2002); also, the PICCs should be taken
into consideration when the hemodynamic changes associated with hepatic steatosis are evaluated in correlation
with the products released by Kupffer cells and sinusoidal endothelial cells (Farrell et al., 2008).
Electron microscopy needs to be further performed to
sustain, beyond the pacemaking potential of the PICCs,
the definition of the PV as ‘‘portal organ.’’
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