ORIGINAL ARTICLE
Telocytes in the Interstitium of Human Exocrine Pancreas
Ultrastructural Evidence
Mihnea I. Nicolescu, MD, DMD*Þ and Laurentiu M. Popescu, MD, PhDþ§
Objectives: Pancreatic interstitial cells are located among acini, ducts,
nerves, and blood vessels. They are essential for pancreas development,
physiology, and for oncogenic microenvironment. We identified cells
with characteristic ultrastructural features of telocytes in pancreatic
interstitium. Telocytes were initially described as interstitial Cajal-like
cells, but it gradually became clear that they were a distinct novel cell
type not directly related to canonical interstitial Cajal cells.
Methods: Serial ultrathin sections of human pancreatic tissue were
studied by transmission electron microscopy. Computer analysis software was used to obtain 2-dimensional compositions from serial micrographs and to perform morphometry.
Results: Pancreatic telocytes appear as small-body cells with prolongations called telopodes. The ultrastructural features of telopodes are
the following: (a) number: 1 to 3; (b) length: tens of micrometers; (c)
moniliform aspect: with podoms (thicker portions) and podomers (thin
segments, with a mean width of 60 nm, undetectable by light microscopy); (d) dichotomous branching forming a network; (e) establish
homocellular and heterocellular junctions; ( f ) release of microvesicles/
multivesicular bodies. Telopodes pass close to blood vessels, nerves, and
pancreatic acinar cells and ducts.
Conclusions: Telocytes are present as distinct interstitial cells in the
exocrine pancreatic stroma. They act as important players in intercellular
signaling via stromal synapses and shed vesicle transfer.
Key Words: telocytes, telopodes, interstitial cells, stromal synapse,
shed microvesicles, exosomes
(Pancreas 2012;41: 949Y956)
P
ancreatic resident cells have either epithelial or mesenchymal
origins. During embryo-fetal period, the epithelial-mesenchymal
interactions are essential for the pancreas development.1,2 Pancreatic stroma is composed of cellular and noncellular tissue framework that surrounds and interacts with pancreas ‘‘resident
cells’’Vendocrine and exocrine compartments, blood vessels,
and nerves.
In 2005, the presence of a novel cell type called ‘‘pancreatic
interstitial Cajal cells’’ or ‘‘interstitial Cajal-like cells’’ (ICLCs)
in the pancreas was reported.3,4 Their existence was widely acknowledged by several laboratories since then.5Y19 Over the
years, such particular cells in the pancreatic stroma have been
mistaken for interstitial neurons,20 endothelial cells,21 Schwann
From the *Department of Molecular Medicine, ‘‘Victor Babez’’ National
Institute of Pathology, Bucharest, Romania; †Department of Cellular and
Molecular Medicine, ‘‘Carol Davila’’ University of Medicine and Pharmacy,
Bucharest, Romania; ‡Department of Advanced Studies, ‘‘Victor Babez’’
National Institute of Pathology, Bucharest, Romania; and §National Academy
of Sciences, Bucharest, Romania.
Received for publication July 23, 2011; accepted October 31, 2011.
Reprints: Laurentiu M. Popescu, MD, PhD, Department of Advanced
Studies, ‘‘Victor Babez’’ National Institute of Pathology, 99-101
Splaiul Independen¢ei, 050096 Bucharest, Romania
(e-mail: [email protected]).
The funding received for this work (to M.I.N.) came partially from the
doctoral research grant CNCSIS BD 457/2006 (National University
Research Council, Bucharest, Romania).
The authors declare no conflict of interest.
Copyright * 2012 by Lippincott Williams & Wilkins
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cells,22,23 ‘‘terminal’’ Schwann cells,24,25 stellate cells,26 ‘‘vitamin A-storing cells’’,27 pericytes,28 or different types of fibroblasts.29 Further ultrastructural observations gradually revealed
that the so-called ICLCs are not directly related to canonical interstitial Cajal Cells (ICCs). Therefore, the novel cell type was
named telocytes (TCs).30Y33 Under the electron microscope (EM),
the TC silhouette is distinctive, with a small oval- or triangularshaped body and several (2Y5)34 specific prolongationsV
telopodes (Tps). These specific unique prolongations are very long
(tens up to hundreds of micrometers), consisting of an alternation of thin segments (podomers) and dilations (podoms).34
Podoms accommodate mitochondria, caveolae, and elements of
endoplasmic reticulum (ER). We report clear electron microscopic evidence for TCs presence in pancreatic stroma.
MATERIALS AND METHODS
Pancreatic Specimens
Surgically resected human pancreatic specimens were
obtained from patients with pancreatic ductal adenocarcinoma.
All patients provided informed written consent, and the institutional ethics committee approved the study. None of the patients
received chemotherapy before surgery. Tumor-free pancreatic
tissue samples (taken from the surgical margin, n1 = 30) were
harvested at the time of surgery from the resected pancreas.
Control samples (n2 = 2) were harvested from nonneoplastic
resected pancreas. For comparison, rat pancreas was also observed (n3 = 2).
Transmission Electron Microscopy
Small fragments of pancreas were processed for transmission
electron microscopy (TEM) according to routine procedures, as
we previously described.35Y38 Ultrathin sections, stained with
uranyl acetate and Reynolds’s lead citrate, were examined using a
CM 12 Philips EM at an acceleration voltage of 60 kV. Digital
electron micrographs were recorded with a Morada 11 Megapixels CCD using iTEM-SIS software (Olympus, Soft Imaging
System GmbH, Germany).
Two-Dimensional Compositions
Images of several neighbor areas were captured at high
magnification, then aligned both horizontally and vertically, and
merged in a bidimensional collage. Alignment and merging were
done using Adobe Photoshop software (Adobe Systems Inc,
San Jose, Calif ).
Digital Color of TEM Images
To increase the visual contrast between several structures
on the same electron micrograph, we have digitally colored
specific elements (eg, telocytes, telopodes, and nerves) to make
them more visible for the untrained eye. All the elements were
carefully hand colored in Adobe Photoshop software (Adobe
Systems Inc) using a Wacom digital tablet (Wacom Europe
GmbH, Krefeld, Germany) to avoid any software mismatches.
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Morphometry and Statistical Analysis
Morphometric data were processed using Macnification
software (Orbicule Inc, Leuven, Belgium). Statistical analysis was
performed using StatPlus:mac software (AnalystSoft, Vancouver,
Canada) and IBM SPSS Statistics (SPSS Inc, an IBM Company,
Somers, NY).
RESULTS
Transmission electron microscopy showed the presence
of interstitial TCs in the pancreatic stroma (Fig. 1). The distinctive features of TCs are their characteristic Tps.
To observe a Tp, one should consider its main ultrastructural features:
1. Telopodes are convoluted processes; so convenient section
planes are needed, in which a larger/longer portion of a Tp
is enclosed.
2. Telopodes are both very long and very thin structures;
therefore, a large and detailed image is required. In other
words, a higher magnification overview is needed. One
should analyze under TEM several neighbor areas and then
FIGURE 2. Interpodomic connections. Human exocrine pancreas:
TEM; TCs digitally colored in blue, shed microvesicles digitally
colored in purple. A, Telopodes establish multiple contacts with
other Tps (red circles). B, Note the ultrastructural differences
between podomers and podoms, the latter being rich in caveolae,
mitochondria (m), and endoplasmic reticulum. An exocrine
pancreatic acinar cell (with rough endoplasmic reticulum
[rER]) is also present. Asterisk indicates a cross-cut Tp.
Scale bar, 1 Km.
TABLE 1. Width of Podomers, Podoms, and Shed
Microvesicles (SMVs)
Podomer
Human
Number
163
Mean, nm
61.04
SEM
1.72
Median, nm
60.00
Mode, nm
50.00
SD, nm
21.90
Minimum, nm
20.00
Maximum, nm
120.00
Skewness
0.486
SE of skewness
0.190
Kurtosis
j0.297
SE of kurtosis
0.378
Pearson correlation
0.947
FIGURE 1. Overview of TCs network in the pancreatic
interstitium. Human exocrine pancreas: TEM; TCs digitally colored
in blue, shed microvesicles digitally colored in purple. A, General
topography of acini and the interstitial TC. Note the small TC
cell body, with a nucleus and several very long and thin Tps. B,
One human pancreatic acinus is circumvented by long Tps
belonging to different TCs. Arrowheads indicate 2 Tps in close
contact with neighbor pancreatic acinar cells. Blood capillary
and a mast cell (MC) are also present.
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Podomer
Rat
Podom
Shed
Human Microvesicles
127
104
6094
58.66
462.31
179.34
1.82
45.71
0.74
50.00
310.00
176.99
40.00*
230.00* 167.18
18.14
466.15
57.89
30.00
100.00
35.58
90.00
2720.00
394.79
0.494
2.999
0.335
0.215
0.237
0.031
j0.423
10.486
0.419
0.427
0.469
0.063
(P G 0.01)
V
V
*Multiple modes exist. The smallest value is shown.
The values of podomeric width in humans and in rats correlate, with a
very good statistic significance. The width of most podomers is below
the resolving power of light microscopy, making the EM an essential
examination tool for the study of telocytes.
The diameter of SMVs measured in the pancreatic interstitium varied
between 35 and 394 nm, with most of the measurements around the
modal value of 167.18 nm. The similar values for median and modal
value suggest the uniform distribution of SMVs and podomers.
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Telocytes in Human Exocrine Pancreas
ably owing to the different spatial orientation of Tp axes.
Images of cross-cut sections of Tps were frequently encountered (Fig. 2). The Tp dimensions, especially their impressive
length, were also in accordance with EM criteria previously
described.30 The uneven caliber (Fig. 2A) is given by the alternation of thin segments, called podomersVwith a mean width
of 61.04 nm, clearly under the practical resolving power of
light microscopyVand dilations (podoms), with a mean width
of 462.31 nm. In Table 1, there is a comparison between the
width of podoms and podomers, as well as a correlation between podomer width values in humans and rats. Podoms accommodate mitochondria, ER elements, as well as caveolae
(Fig. 2).
Telocyte Networks
Two-dimensional reconstructions from serial photos suggest
the existence of TC ‘‘plexuses’’, resulted from branching Tps in a
dichotomous pattern. Telopodes can be found circumventing the
acinus in Figure 1. The intra-acinar (among the exocrine secretory acinar cells) and interacinar TC meshes are intermingling,
forming a complex 3-dimensional network (Figs. 1Y3). A TC
establishes multiple contacts with other TCs (Figs. 2, 3), as well
as ‘‘stromal synapses’’40 with mast cells (Fig. 4A) or macrophages (Fig. 4B). For lengths of hundreds of nanometers
(Figs. 3, 4), the synaptic cleft is approximately 20 nm or less.
Telocytes extend their slender Tps, bordering neighbor structures: blood vessels (Fig. 5A), nerve fibers (Fig. 5B), or ductal
elements (Fig. 6B). A close connection with a stellate cell near
a pancreatic endocrine islet is shown in Figure 6A. Figure 7
shows a Tp passing in the vicinity of a blood vessel, a nerve,
FIGURE 3. Interpodomeric connections. Human exocrine
pancreas: TEM; TCs digitally colored in blue, shed microvesicles
digitally colored in purple. A, Note the long (3.22 Km, dotted
yellow line) linear plain contact between podomers of 2 Tps
(Tp1, Tp2) in their intra-acinar trajectory in human exocrine
pancreas. B, Several Tps located between an acinar cell and a mast
cell, bordering both of them. They establish a close intertelopodic
convoluted plain contact (dotted yellow line) 8.63 Km long. A
multi-vesicular body (arrowhead) is present at a Tp bifurcation.
align and merge the captured images both horizontally and
vertically. The reconstructed collage will show an area that
could not have been directly captured entirely unless at
lower magnification.
As it has previously been pointed out by Zhai et al,39 there
are EM details that will not necessarily be represented in the
frame-grabbed images, and this might lead to the choice of a
higher magnification at the expense of overview. Taking into
account that any increase of the magnification leads to a
smaller field of view, the only possible way to achieve more
information in a given area is by merging high-magnification
images of small areas into a larger reconstruction showing
a detailed large area. One may see the difference in observing shed microvesicles at lower (Fig. 1) and higher (Fig. 2)
magnifications.
Usually, we found TCs with up to 3 Tps, but the most
common encountered image was of cells with 2 Tps, presum* 2012 Lippincott Williams & Wilkins
FIGURE 4. Stromal synapses. Human exocrine pancreas: TEM;
TCs digitally colored in blue, shed microvesicles digitally colored
in purple. A, Multi-contact (bright yellow) and ‘‘kiss-and-run’’
(bright red) stromal synapses between a Tp and a mast cell.
Note that the contacts are established at both podomic and
podomeric levels. B, Multi-contact stromal synapse between a
long Tp and a macrophage. Note also a multi-vesicular body.
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and exocrine pancreatic secretory (acinar) and excretory (ductal) structures.
Telopodes and Shed Microvesicles
The homogeneous distribution of podomers caliber measurements (Figs. 8A, C) supports the idea of a tubular shape of
these segments (so sectioning angle does not affect too much
the diameter of longitudinal sections). On the contrary, the variable shapes of podoms (Fig. 8B) lead to more spread values of
caliber measurements, depending on section angle, podomic area
enclosed in the section plane, distance to the proximal/distal
podomeric segment, and so on.
We also noted the abundance of microvesicles (Figs. 2B,
6A) or multivesicular bodies (Figs. 3B, 4B, 7) budding from
Tps. The vesicles were round or oval in section, with a mean T
SD value of their long diameter of 179.34 T 57.89 nm (n =
6094; Table 1). This figure places them in the shed microvesicles category (SMVs).41,42 The normal curve for these values
has a single-bell shape (Fig. 8D), indicator for a homogeneous
population. The release of these vesicles is not at random. Most
FIGURE 6. Telocytes near stellate cells and pancreatic ducts:
TEM; TCs digitally colored in blue, shed microvesicles digitally
colored in purple. A, Pancreatic stellate cell (digitally colored in
brown) in close relation to several Tps (digitally colored in blue).
Note also abundant microvesicles. Human endocrine pancreas. B,
Parallel Tps (digitally colored in blue) bordering cells from the walls
of pancreatic intercalated and intralobular ducts. Rat exocrine
pancreas.
FIGURE 5. Telocytes near blood vessels, nerves and collagen
fibers: TEM; TCs digitally colored in blue, shed microvesicles
digitally colored in purple. A, Several Tps (digitally colored
in blue) are passing very close to endothelial cells. Note
that Tps establish contacts with other Tps (podomer-podomer
and podomer-podom). Note the similar diameter of podomer
segments and collagen fibrils (arrowhead). Human exocrine
pancreas. B, Telopode neighboring a nerve (digitally colored in
green) in pancreatic interstitium. Inset shows nascent shed
microvesicles (arrows). Also present transversal- and cross-cut
collagen fibrils. Rat exocrine pancreas.
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FIGURE 7. Integrative role of telocytes. Rat exocrine pancreas:
TEM; TC digitally colored in blue. Note the same Tp bordering
blood vessel (digitally colored in red), nerve (digitally colored
in green), and pancreatic acinar and ductal cells. Also note a
multi-vesicular body (digitally colored in purple).
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Telocytes in Human Exocrine Pancreas
FIGURE 8. Telopodes and shed microvesicles in pancreatic interstitium. The measured width (in nanometers) of Tps in humans
(A, podomers; B, podoms) and in rats (C, podomers) shows a homogeneous distribution of values. The normal curves were overlaid.
Note similar values and single-bell shape for values of podomer widths in humans (A) and rats (C), and the wider-spread values for podoms
(B), due to the various podom shapes and section angles. In addition, most of the podomers are below the resolving power of light
microscopy.
of the SMVs were spotted around Tps (52.62%), in comparison with 10.95% near the TC cell body or 36.43% scattered at
some distance from TCs. No inflammatory infiltrate was found.
DISCUSSION
The importance of mesenchymal cells during the embryonic stages of pancreatic development is well known.1,2 We
show here that TCs, a subpopulation of interstitial (mesenchymal) cells, are vivaciously active also in adult life. They establish
stromal synapses, presumably the main intercellular communication mechanism of TCs.
Communicating via SMVs with other cells might represent
the alternative to stromal synapses for a telecrine/remote noncontact cellular cross talking. They are not just inert stromal
elements but active participants in regulating specific microenvironment(s). The podomic ‘‘trio,’’ consisting of mitochon* 2012 Lippincott Williams & Wilkins
dria, endoplasmic reticulum, and caveolae, is involved in Ca2+
movements as organizing centers for signal transduction.43,44
This particular structure of the podoms offers the energetic
(mitochondria) and functional (proteins from ER) support that
allows the extension of Tps in the extracellular environment
(see Tps trailing in TCs cell culture34).
Telopodes differ from axons both morphologically (moniliform versus uniform caliber aspect under EM) and structurally
(axons do not contain any ER. The neuronal ER is located
in the perikaryon, implying an almost linear correlation between the axon length and the neuronal soma size to ensure
proper axonal function). The Tp width in its thinnest region,
at podomeric level, is comparable to collagen fibrils (Fig. 5).
We believe there is also another distinction between the two
cellular prolongations mentioned earlier, concerning the possible variable position of Tp using podomers as mobile
segments.
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953
Pancreas
Nicolescu and Popescu
To elucidate the possible ultrastructural confusion between canonical ICCs and TCs, we present here a comparative
table (Table 2), along with a few explanatory remarks (for
comparison, see ICC ultrastructure described in Suciu et al,37
Popescu et al,45 and Pieri et al46). One may notice cells that only
resemble the canonical ICCs but fail to meet several established ICC diagnosis criteria. Initially, these cells were named
interstitial Cajal-like cells (either ICLCs4 or pancreatic ICCs3
or even ICC-LCs19 to list only examples for pancreatic cells).
We previously explained the rationale for a new term for labeling this particular cell type that has its own ultrastructural
panel of features.30,32,33 Therefore, we reiterate our point of
view that cells should only be called ‘‘-like’’ in cases where there
is not (yet) any properly defined term for their kind; but in this
case, the term exists and it is telocytes. Referring to Cajal cells in
labeling these cells became obsolete because there are many
differences in all cellular compartments between the two cell
types (Table 2). The difference between ICC processes and Tps
of TC is striking.
The peculiar TC prolongations’ unique profile starts from
the cellular emergence where the diameter is already very small.
By contrast, ICC prolongations have a wider emergence caliber,
and they gradually become thinner.
The defining attributes continue to stack up when we look
at the alternation of small-caliber segments (podomers) and
dilated knobs (podoms), giving the telopodes their trademark
moniliform aspect (Fig. 2A). Finally yet importantly, the excep-
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tional length of TC cytoplasmic processes (telopodes) puts them
in pole position among all nonneural cells. Telocytes are the cells
with the longest known prolongations besides some neurons.
We found two different patterns of Tp ultrastructural organization. The most common one was when the Tp caliber
gradually increased from podomer to podom (Fig. 4A), and the
other case was when podomers arise abruptly after the podomer
endings (Fig. 3A). We would like to mention that Tps belonging
to the first described category presented increased overall caliber
(at both podomeric and podomic levels) compared to the Tps
from the second category.
We present here the existence of TCs in pancreatic interstitium, and as far as pancreatic ICCs existence is concerned, we
did not find any cell to meet all the ICCs criteria in the studied
regions of human or rat pancreatic interstitium. This does not
exclude the ICCs presence in the human/rat pancreatic stroma
but states the fact that ICCs might not be present in all interstitial
locations (our study being focused on periacinar/small caliber
ducts areas). Taking into account both the novelty of TCs and
ultrastructural differences between TCs and ICCs, we noticed
that fragments of TCs/Tps appeared frequently in EM images
in the literature but were either mistaken or overlooked. For
example, in a recent paper,19 in Figure 3A (and also in the
magnified field [Fig. 3B]) an abundance of Tps can be identified, as well as a TC in Figure 5C of the same paper.
The actual function(s) of TCs remain to be established.
These cells possess the features compatible with nursing
TABLE 2. Ultrastructural Features of Telocytes and Canonical ICCs (Based on Our Data and on the Following References:
Suciu et al,37 Popescu et al,45 and Pieri et al46)
Telocytes
Cell body
Size
Shape
Cytoplasm
Nucleus
Nucleolus
Golgi complex
Endoplasmic
reticulum (ER)
Cytoskeleton
Mitochondria
Caveolae
Basal lamina
Prolongations
Small
Spindle/oval/triangular
Small amount
One, oval/rod-shaped
Rarely visible (one)
Small sized
Scarce smooth ER, ER located in podoms
Thin and intermediate filaments
Located mostly in podoms and in the cell body (few)
Present
Absent or discontinuous
& 2Y5 telopodes, dichotomic branching pattern,
& Convoluted, forming 3D networks
& Diameter thin at emergence from the cell body,
overall moniliform aspect
Telopodes
Podomers
Podoms
& Very thin (mostly below the resolving power of light microscopy)
& Very long (tens to hundreds of micrometers)
Small-caliber segments of telopodes, with a mean width
approximately 60 nm
Dilated portions/knobs of telopodes, accommodating
caveolae, mitochondria and ER, with a variable width
(in this case approximately 460 nm)
Canonical Interstitial
Cells of Cajal
Large
Spindle/oval
Large amount
One, oval-shaped
Frequently visible (one)
Normal sized
Extended smooth ER, few cisternae
of rough ER
Thin and intermediate filaments
Many, especially around the nucleus
Many
Present
& 2 or more prolongations, with
several ramifications,
& Intermingling
& Diameter thick at emergence from
the cell body and gradually
decreasing
Absent
Absent
Ultrastructural differences between TCs and canonical ICCs are visible in all cellular compartments (cytoplasm, nucleus, and plasma membrane), but
the most striking difference is the presence of telopodes and their specific unique characteristic.
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several other cell types and/or modulating specific microenvironments.30,33,47 Their long Tps (Fig. 1) and homocellular (Figs. 2, 3) and heterocellular (Figs. 4, 5) connections
lead to the establishment of a structural and functional intraacinar and interacinar networks, with attributes and roles yet
to be fully discovered. Branching pattern of Tps might enhance
the cellular signaling of TCs in the interstitial microenvironment. The association of nerve fibers with occasional interstitial cells was also reported in other mammals.48
The ductal labyrinth49,50 of the exocrine pancreas has less
periductal TCs than the acinar area. For comparison, in major
salivary glands such as the parotid and the submandibular
glands, the disposition is reversed, with TCs being more frequent
around ducts than interacinar.51 Nevertheless, we observed Tps
in close relation with pancreatic ducts of different calibers
(Fig. 6B). It is known that acinar units composed of several
hundreds of cells function together.52 Therefore, it is tempting
to speculate that the Tp-specific ultrastructure, circum-acinar
layout, and their close relation with acinar cells may help regulate a common calcium microenvironment for these cells.
Evidence of similar cells in the pancreas of other mammals
was recently gathered,19 but our study may be the first that
describes TCs in human pancreas. We have also shown EM
micrographs of analyzed rat pancreatic tissue, in which the
presence of TCs was acknowledged.
The 3-dimensional lattice supported by Tps is connected
with both nervous and vascular networks, as well as with specific local cell population by either stromal or telesynapses
mediated by the SMVs mentioned earlier. After measuring more
than 6000 vesicles (Table 1), the morphometric data we obtained
proved that we were facing a homogeneous population of extracellular vehicles in the SMVs category. The SMVs may function as ‘‘multi-purpose carriers,’’ involved in communication,
protection, and exchange of genetic information.53 Intercellular
communication is required for a proper coordination between
different cell types within tissues.42,54,55 Further molecular paneling of TCs may lead to the development of targeted molecular therapy for treatment of current low-prognosis diseases such
as pancreatic adenocarcinoma.56Y58 Telocytes might be useful for
delivery of biological molecules or for sensing changes in stromal microenvironment, and also in future understanding of cellular basis of the pathophysiology of chronic pancreatitis and
other pancreatic diseases.
ACKNOWLEDGMENTS
The authors thank Mrs Maria Buzatu and Prof Nicolae
Ionescu for their constant help.
Telocytes in Human Exocrine Pancreas
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
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