OF THE ROMANIAN ACADEMY Research article THE CORDOCYTE LEON DĂ NĂILĂ National Institute of Neurology and Neurovascular Diseases, Bucharest, Romania,… [625361]

THE PUBLISHING HOUSE MEDICINE
OF THE ROMANIAN ACADEMY Research article
THE CORDOCYTE
LEON DĂ NĂILĂ
National Institute of Neurology and Neurovascular Diseases, Bucharest, Romania, Clinic of Neurosurgery
Corresponding author : Leon DĂNĂILĂ, E-mail: [anonimizat]
Received May 27, 2014
My research work, which led us to discover this cerebral cell (Cordocyte) has started in the 2000
years, when I have highlighted it for the first time, during a study upon clarification of some
undiscovered aspects of cerebral at herosclerosis. In 2005, I have in itiated the publishing our results in
two atlases and at Cape Town congress in 2006. This work is based on data analysis by light and
transmission electron microscopy of the surgical cases operated by me in the last 13 years. We
examined cortical arteries and veins, perivascular areas with old hematic masses, vasculogenetic foci,
broken large vessels, moyamoya di sease, thromboses, tumors and cer ebrovascular malformations, to
identify and characterize different phenotypes belonging to a new interstitial cell re cently described
ultrastructurally in the brain and here, named cordocyte. Also, we attempted to identify and characterize precursor/stem cells for cordocytic lin eage in the perivascular areas, within perivascular
nerves, choroid plexus and pia mater (now c onsidered a cordocytic-vascular tissue). This
cytohistopathological study illustrates and explains some facets of cordocytes-stem cells cooperation
around on the fundamental role of cordocyt es in response to vascular injuries.
Key words : human brain, vessels, cordocytes, stem cells ultrastructure.
INTRODUCTION
History
My research is based on the well-known fact
according to which, the brain is devoid of
lymphatic tissue and lymphatic circulation.
Considering this phenomenon, I asked myself if
it is possible that its functions are taken over by
other elements of the central nervous system (CNS) which had not been known until today.
As a neurosurgeon, I had studied day by day,
with great patience and attention, with the help of the optical microscope and of the electron microscopy, all the expansive processes and the cerebral biopsies harvested from the patients I had operated on.
In this way, beginning with 2000, I had
observed the existence within the brain of a thin and elongated interstitial cell with a protective and defensive role against the various internal and external aggressions, of the most noble and most complex structure in the universe – the brain (Danaila et al., 20
00; Danaila et al., 2002 a, b;
Danaila et al., 2003 a, b; Danaila et al., 2004 a, b;
Danaila and Pais, 2004; Danaila et al., 2005).

Proc. Rom. Acad., Series B, 2014, 16(2) , p. 83–102 The referred to observation, which
I had
initially considered to be insufficient, did not allow me to make public this new morpho-functional cerebral cytological entity.
It wasn’t until the year 2005 when, following
the positive rendering evident of the most important morphological (Figure 1) and physiological
features, about which I did not have any doubts
anymore, I had made public and I had described in two atlases the new cerebral cell I had discovered (Danaila et al. , 2005; Danaila and Pais, 2005).
I had postponed the official announcement of
my discovery because the analized cell was very thin and thus below the resolution of the optical microscope.
The enormous amount of the material which
required analyzing had made me to take on as collaborator the biologist Viorel Pais who, although

Leon Dănăilă 84

Figure 1. An arteriovenous malformation containing multip le long cordocytes arranged in parallel (arrows).
he had never worked in the Neurosurgery
Department of the National Institute of
Neurovascular Diseases in Bucharest, had
sufficient experience in this field.
After several years, he had been pensioned off
from the Ultrastructural Pathology Department of “Victor Babes” National Institute of Research
Development in the Pathology Domain and
Biomedical Sciences in Bucharest, and he had died on the 2
nd of July 2014.
Anyhow, by having enough time at his disposal,
he had been a real help for me in the selection of
the figures, in their arranging into the atlases and in
their drawing up, as well as in the carrying into effect of several scientific papers related to this problem, as it follows.
In 2006, we had presented the results of our
research at the World Congress on Stroke in Cape
Town (Danaila and Pais, 2006), and in 2008, at the
6
th World Stroke Congress in Vienna (Danaila and
Pais, 2008).
The first synthesis paper with reference to the
morphology and the physiology of the cordocyte
(already known at that time) had been published in
2011 (Danaila and Pais, 2011).
Subsequently, in 2012 and in 2013, Pais Viorel,
Danaila Leon and Pais Emil had also published another two scientific papers on this topic in the “Ultrastructural Pathology” medical journal (Pais
V, Danaila L and Pais E, 2012; 2013).
Emil Pais, who appears as the third and the last
author of several recent sci entific papers, but not of
the atlases in which it is stored our entire research
work relating to the cordocyte, the cellular death,
the angiogenesis, etc., did not have any
contribution to the research conducted by Leon Danaila and Viorel Pais.
He had been added as the third author by his
father, in order to become employed by a medical
institution in the United States of America, where
he had emigrated immediat ely after graduating the
University of Medicine and Pharmacy in Bucharest.
In 2014 we had published an optical and
electron microscopy atlas which comprises new
and innovative data with reference to the
morphology and the physiology of the cordocytes in the human brain (Danaila Leon and Pais Viorel, 2014).
We had undertaken this study because this
interstitial cell, which is similar, but not identical to the interstitial cell of Cajal, has a wide cerebral distribution and multiple functions which had not been reported in the literature by any other author.

The Cordocyte 85
We consider it to be a genuine maestro in health
and diseases because of its biological potential
within the cerebral parenchyma, in the areas surrounding the blood vessels, in the choroid plexuses, in the pia mater, etc.
MATERIAL AND METHODS
This work is based on the data analysis by light scanning
and transmission electron microscopy of the surgical cases
operated by Danaila during the last 13 years.
The ages of the patients from whom there had been
harvesteed the cerebral bioptic material had been between 4
and 90 years old.
The analyzed pathological processes had included
thromboses of the carotid system, cerebro-vascular
malformations, aneurysms, primary hematomas, Moyamoya disease, perivascular hemorrhag es, infarctions, traumatic brain
injuries, metastatic brain tumors, tuberculomas, cysts, tumors (tumors of the normal chor oid plexus, pineocytomas,
germinomas, medulloblastomas, glioblastomas, astrocytomas,
schwannomas, meningiomas, he mangiopericytomas, lymphoma
craniopharyngioma, hypophyseal tumors, chordomas), abscesses, cysticercosis, hydatidosis, etc.
The normal cerebral cortex and the white matter had been
harvested from the patients which had been operated for unbroken cerebral aneurysms (Danaila and Pascu, 2001; Danaila et al. , 2002; Danaila et al. , 2006; Danaila and
Ștefănescu, 2007; Danaila et al. , 2008; 2009; 2010 a, b, c;
Danaila, 2012; Danaila et al. , 2012 a, b, c; Danaila, 2013 a, b,
c; Danaila et al. , 2013; Danaila and R ădoi, 2013; Danaila and
Pascu, 2013).
The samples which had been studied under an optical
microscope had been fixed with 2.5% buffered glutaraldehyde
and post-fixed with 1% bu ffered osmium tetroxide,
dehydrated in alcohols and embedded in resin epoxy (Epon
812). There had been cut sections with a thickness of 4-6 μ
using an ultramicrotome which had been then mounted on glass slides, stained with 1% toluidine blue, and examined
using optical microscopy. There had also been cut with the
ultramicrotome multiple ultrathin sections, with a thickness of 70 nm, which had been then treated with 2% uranyl acetate, as well as with Reynolds lead citrate solution. The specimens were then examined using the JEM 1200 EX (JEOL) transmission electron microscope.
The electron micrographs had been processed on a
computer and then converted into images.
Ultrastructurally, there had been identified, characterized
and compared both undifferentiated cells and well-differentiated cordocytes found in different locations, from the
outer cerebral cortex to the choroid plexus, and in areas with old hematic masses, vasculogenetic foci, heterotopic neural
tissue, encapsulation, brok en arteries and abnormal
proliferations, such as microtumors.
We had demonstrated the ex istence of ph enotypical
changes of the cells, and our findings had especially shed light on the roles of these cells which might facilitate the beneficial
actions and delay the patholog ical processes, they being
involved in the fundamental pro cesses of the development of
the central nervous system. RESULTS
Several new histopathological features
The protective role of the pia mater cordocytes
The cordocytes, which form the pia mater
together with the with blood vessels, are involved
postnatally in the normal corticogenesis (which had been demonstrated in the cerebral ectocortex), in the maintenance of the appropriate pericortical
microenvironment, in the vasculogenesis, vasomotion
and vascular repair / remodeling, in the inhibition of the hematic invasion into the brain parenchyma as physical barriers, especially in the hypertensive human individuals, in the inhibition of the
microtumoral growth and of any aberrant cellular
migration towards the cerebral cortex, etc. (Figure 2).
Thus, the pia mater is composed of cordocytes.
This assembly of cordocytes as the ultimate and active defender of the cerebral cortex and of the cortical vessels is a very dynamic structure, it
undergoing numerous phenotypical modulation
changes and accompanying various events, both in healthy individuals and dur ing pathological processes,
as a barrier within the immune surveillance.
The cordocytes and the blood-brain-barrier (BBB)
The blood-brain-barrier concept is based on the
fact according to which the vital dyestuffs introduced into the blood flow do not color the brain.
Therefore, the blood-brain-barrier is the
morphofunctional system which selectively
regulates the access and the exit of the biological
substances and of the cells, in order to control and to preserve the normal microenvironment, the morphology and the physiology of the brain.
To that effect, we had ascertained that not only
the close interendothelial junctions have such a
role, but the entire wall of the capillaries, of the
arteries and of the veins are overprotected on the outside by well defined layers of cordocytes. (Figures 3 and 4).
The cordocytes prevent the access into the brain
especially of the red blo od cells, whose degradation
products have a nocuous effect not only on the cerebral parenchyma, but also on the blood vessels, in which they have a spasmodic effect.
Its consequences, which can sometimes be even
fatal, can be found in the patients with subarachnoid
hemorrhage.
The cordocytes block the uncontrolled
spreading within the brain of the red blood cells

Leon Dănăilă 86
which cross the intercellular junctional complexes
which tightly connect the endothelial cells among
themselves.
Our microscopic observations had been focused
on the periarterial areas.
In this way, we had observed that the
extravasated red blood cells are detained by the
cordocytes either through adhesion or through
catching. Finally, the red blood cells which had
been loaded on the cordocytes are hemolyzed.
Whenever the protective cordocytic network is
overwhelmed by the large quantity of red blood
cells, or when these die, there are generated self-
signals which concentrates numerous perivascular
stem cells in the injured area (Figure 5).
In such situations, in the respective area there
can be found unidentified cells, transitional forms
and well defined cells.
Generally, most of our body is constantly
renewed. The adult neurogenesis is the production of new functional neurons in the adult brain
(Figure 6, adapted from Altman and Dass, 1965).
The cordocyte and its antitumoral role
The defensive means of the human body against
cancers are equally numerous as their causes.
Therefore, during his or her lifetime, an
individual can suffer and can be cured of cancer several times.
Actually, the human body can sometimes
survive even the most terrible diseases.
Among the multiple defensive possibilities of
the brain against the abnormally proliferating cells
we can also find the cordocyte.
In such circumstances, every single cell which
usually surrounds an artery can be activated, and
they will position themselves in front of the
abnormal cellular mass, with the nuclear long axis
perpendicular to the advancing cell mass (Figure 7).
This peculiar inhibitory role of the abnormal
cell proliferations is demonstrated by this cell type
in the genuine tumoral cases, when large
perivascular formations are closely surrounded by
cordocytes, which inhibit and delay both the cell
growth and their movement (Figure 8). This
property to impede / delay both the cell growth and
any motion is easily observable in the cases with
arteriovenous malformations, where the cordocytes seem to have an efficient role in controlling the
development of the neural tissue, closely
surrounding all the neuroepithelial cells, and
extending their filopodia towards the target cells.
Moreover, overlapping cordocytes form a thick
barrier between the neuroepithelial and the
lymphocytic population, with the lymphocytes
being separated from the neural cells (Figure 9).
In the analysis performed by Pais, Danaila and
Pais (2013) there had been observed certain
important aspects which we shall present as follows.
Thus, we had ascertained the interesting fact
that the tumor formation is often surrounded by a thin basement membrane consisting of fibrils. The
referred to thin fibrils surround each one of the
tumoral cells, but not the immune cells infiltrated within the tumor mass.
The presence of the long and thin protrusions of
the cordocytes around the microtumor suggests their role of antitumoral barrier.
Nevertheless, this barrier is missing here and
there, while in other areas, where it is degenerated, there are found numerous peripheral thin
connective fibrils.
In the zone surrounding the microtumoral mass,
with areas of autophagy, the white matter is
degenerated, the axons are caricatured, the oligodendrocytes are in an apoptotic phase, while
the microglial cells are loaded with autophagosomes, secondary lysosomes and vascular cytoplasmic areas.
At the analysis of the transmission electron
microscopy images of another tumoral node located within the white ma tter, in a female patient
with a traumatic brain injury, we had observed an increased density of cells which appeared to be derived from the perivascular cells and the modified endothelial cells of the staghorn-shaped vessels.
These proliferated polygonal cells which
surround the endothelial cells in the so-called
staghorn pattern are characteristic for a
hemangiopericytoma, which can metamorphose later into a true intraparenchymal tumor.
The traumatic injury could have been an
etiological factor for the tumor.
In conclusion, in some tumors, the cause can be
represented by the traumatic brain injury.

The Cordocyte 87

Figure 2. Pia mater, there can be seen cordocytes surr ounding the pial vessels and cove ring the cortical surface.

Leon Dănăilă 88

Figure 3. A portion from a cortical ve in showing long cordocytes at the level of the vascular surface.

The Cordocyte 89

Figure 4. Multiple long cordocytic prolongations with adherent erythrocytes and a cytogenetic focus
where can be seen new interstitial cells intermingled with vascular cells, in a hypertensive patient.

Leon Dănăilă 90

Figure 5. Periadventitial cells (arrow head), multiple and long cell prolongati ons with adherent erythrocytes
(right arrow), and a cytogenetic focus containing stem cells / precursors cells where can be seen new interstitial cells,
in a hypertensive patient (lower arrow), ( OM  200).

The Cordocyte 91

Figure 6. Altman’s first image of an adult-generated neuron (adapted from Altman and Das, 1965).

Figure 7. Abnormal cell cord around the vascul ar wall formed by cordocytes, which have an inhibitory role on the cell movement.
This seems to be a special function of this cellular type, which comes in front of the abnormal proliferated cells with a chara cteristic
positioning (arrow), ( OM 400).

Leon Dănăilă 92

Figure 8. A solid and contorted cellular cord surrounded by cordocyt es which impede the cell migration and proliferation in a c ase
with a cerebral metastasis of a carcinoma. The arrow indi cates a cordocyte firmly attached to the abnormal cells. ( OM 200).

Figure 9. Neural tissue surrounded by a dense lymphocytic inf iltrate, in a case with an arteriovenous malformation. All the
lymphocytes seem to be se parated from the neural tissue through this thick barrier formed by cordocytes. ( OM 400).

The Cordocyte 93
The repair and the regeneration of the cerebral
blood vessels with the help of the stem cells, of the
undifferentiated cells and of the mature or well-
differentiated cordocytes
Following the study of the biopsies we had
harvested from the patients with high blood
pressure, from those with arteriovenous
malformations (AVM) or venous malformations,
as well as from those with arterial thromboses, we
had ascertained the presence of the ruptures
(Figure 10) and of the defects of the vascular wall (Figure 11) and the existence of the cytogenetic
(vasculogenetic) foci.
In the cases of perivascular hemorrhages, the
mature cordocytes surrounding the arteries and the veins have most of the times spatial and temporal
relations with the undifferentiated cells and with the mesenchymal stem cells.
The cordocytes not only make a supportive
interstitial network for the stem cells, but they act as regulators and modulators for the different
cellular types in all the stages of the processes, they
being particularly sensitive to any local damage.
In this kind of situations, some of the
cordocytes remain in the proximity of the adventitial layer, while others move to the perivascular space, where they have close
relationships with the isolated undifferentiated
cells and with the mesenchymal stem cells from which emerge new cordocytes (cytogenetic foci) in
order to clean the perivascular spaces.
Al the small cytogenetic foci contain both
progenitors of the vascular cell lineage and precursor cells for the cordocytic lineage. On the
other hand, all the cytogenetic foci with only several precursor / stem cells are already
surrounded by one or tw o well-differentiated
cordocyte layers, fact which suggests their
important morphological roles in the early events
of the vascular morphogenesis.
In this way, the well-differentiated cordocytes
gradually eliminate the red blood cells from the future vasculogenetic foci.
However, in some arteriovenous
malformations, multilayered cordocytes surround the proliferating precursor / stem cells, whereas the
hematic mass is surrounded by a single layer of well-differentiated cells, due to the different
cytokinetic mechanisms which are present in the
different cell types.
Normally, the long and thin cordocyte
prolongations which surround the nascent vessels suggest a controlling role of the proliferation, migration and differentiation processes. The cordocytes gradually orchestrate all the
cellular events in the vasculogenetic sequence, because they are in direct contact with the stem cells and with the different progenitors, and
surround each cytogenetic focus, indifferent of its
age, until the formation of the mature vessel.
All cellular divisions, migrations, and
differentiations are in direct relation with the well-differentiated cordocytes which send thin prolongations toward the target cells, or surround
the massive formations which contain many
differentiating cells originating from the hematopoietic stem cells or from the perivascular
mesenchymal stem cells.
When the well-differentiated cordocytes are
absent, the precursor / stem cells are spreading in
the space and not in the vascular lineages.
In the vascular segments with narrowed lumen
or with occlusions, there can be observed at the vascular surface an accumulation of precursor /
stem cells in association with cordocytes, or cytogenetic foci where only the cordocytes are
present. Thus, these cytogenetic foci are positioned
in the immediate vicinity of the disrupted vascular walls.
These are prompt reactions of the protective
cells which are located around the vessels (Figure 12).
In the transmural erythrodiapedesis, sometimes
the tunica adventitia is thickened and contains
numerous precursor / stem cells, but not
differentiated cells, cordocytic phenotypes, or
vascular lineage.
The remodeling begins with the mobilization of
the stem cells, followed by the proliferation and the migration toward the place of rupture of the differentiating cells of cordocytic lineage, and
finally ends with the new cordocytic coverage of
the vascular surface.
These spatial and temporal modification
mechanisms are regulated by the cellular dynamics
and morphology.
Responsible for such mechanisms are the well-
differentiated cordocytes, because they come in direct contact with the stem cells through their long and thin prolongations.
Moreover, other well-differentiated cordocytes
come to the damaged place, fact which suggests precise and specific signaling pathways.
Finally, when the arterial rupture is resolved
through the cell cooperation, which also includes the smooth muscle cell activity within the tunica
media, a new layer of cordocytes and other
elements and cells covers the vascular surface (Figure 12).

Leon Dănăilă 94
However, cordocytes playing a key role are
observed in some cases with arteriovenous
malformations in which the tunica media is lacking in some of the vascular segments.
In this areas, well-differentiated cordocytes
gather stem cells which become adherent to the cell membranes in the damaged area (Figure 12).
In the veins, there ar e found stem cells which
are clustered together through long prolongations and short filopodia of the local cordocytes at the
level of the damaged vascular wall (Figure 13).
Additionally, other mature cordocytes,
reinforced by collagen fibers they produce
themselves, are directed toward a crossing cell
column which prevents the venous wall to collapse due to the focal degeneration.
In the patients with thromboses, there is also
present a perivascular reaction of the cordocytic lineage, with polymorph nuclei, in conjunction
with mature cordocytes.
Now there can be identified stem cells in
symmetrical divisions in small cytogenetic foci, as well as undifferentiated or morphologically
transitional cells and matu re or well-differentiated
cordocytes, with their characteristic ovoid nucleus
and prominent and marginal nucleolus.
However, these protective cells occupy a
peripheral position, at the vascular surface, surrounding the different cellular foci, in direct
contact with the fibroblasts and the macrophages in the perivascular areas with new arterioles and
numerous foam cells.
A thrombosed branch originating in the middle
cerebral artery had showed the involvement of the cordocytes, both during the early vasculogenetic
events and in the maturing vessels.
Matured and interconnected cordocytes surrounded
the totally thrombosed main artery, and there could be seen both the incipient cytogenetic focus (Figure 14) and the collateral vessels in formation.
The cordocytes are always distributed to the
peripheral zones of the cytogenetic / vasculogenetic foci to support the cellular actions and to protect
the delicate cellular building, they producing
themselves an amount of collagenic extracellular matrix as supporting connective material.
The referred to vasculogenetic process attracts
from the beginning other cordocytes which position themselves at the periphery, so that in the
end, at the exterior of the mature vessels there is
sometimes an excess of cordocytes showing apoptosis processes (Danaila et al., 2002).
At another level, a thick cell column emerges
from the other adventitial layer including cordocytes and a few stem cells. In the core of nascent vessels it is visible a
segregation of the differentiating cells, some of them becoming endothelial cells, while others evolve into smooth muscle cells. The surplus cells,
either endothelial or smooth muscle cells, may
undergo apoptosis or auto schisis processes which
are identified using the electron microscopy.
However, the continuous involvement of the
cordocytes is evident in all the stages of vascular morphogenesis. Whenever a vasculogenetic focus
increases in size, it is surrounded by interconnected
mature cordocytes which keep inside all the cells (both undifferentiated and di fferentiated, i.e., stem
cells, progenitors of endothelial cells, smooth muscle cells and fibroblasts) which participate in histoarchitecture of the vascular wall.
Our electron microscopy observations
demonstrate a very close rapport between the perivascular cordocytes and the stem cells in the
early phase of collateral v asculogenesis, when the
cordocytes surround from the beginning until the
end all the proliferating and differentiating cells
during their maturation process towards
endothelial cells, smooth muscle cells, fibroblasts and well-differentiated cordocytes.
Therefore, it is clear that the cordocyte act as a
guide and as a protective cell for a cytogenetic / vasculogenetic focus, despite the reduced number
of stem cells within the vascular niche (Figure 15).
The principles which control the embryonic
stem cells, the proliferation versus differentiation,
the paracrine mechanisms, as well as the identification of the different messenger molecules they secret themselves, remain to be comprehensively established.
According to Belting and Wittrup (2008), the
novel pathways for the cell to cell communication involve nanotubes, exosomes, apoptotic bodies, and nucleic acid-binding peptides.
In conclusion, the perivascular cordocytes
cooperate closely with the stem cells in the vascular repair and in de novo vessel formation through cell proliferation and cellular differentiation.
The cordocytes as anti-hematic barrier
In the cases with recent hemorrhagic foci, we
had ascertained in their periphery the presence of a long and thin cordocyte with the role of anti-hematic barrier (Figure 16 a, b).
The lysed cells from the hematic mass probably
generate chemoattracting agents for the referred to delimitating and neuroprotective cordocytes.
The neuroprotective action is demonstrated by
the fact that there cannot be found any red blood
cells beyond the cordocytes.

The Cordocyte 95
The cordocytes in the human brain associated with
inflammation-carrying extracellular vesicles
The investigations had been performed through
transmission electron microscopy (TEM), on the
biopsies harvested by me (Danaila L) from the
patients with intracerebral cysts, parenchymal hemangiopericytomas, arterial thromboses,
Moyamoya disease, meningiomas, glioblastomas
and other cerebral tumors.
In these types of cases, besides the cordocytes,
we had also ascertained the presence of a number of exosome-like spherical vesicles (30–120 nm) and of microvesicles (100–1,000 nm).
The vesicles derived directly from the
membrane, as well as the exosomes originated from the exocytosis of the multivesicular bodies,
are dedicated to the intercellular information
transport, to the biogenesis, the preservation of the normal cell functions and to the reparation of the
pathological foci.
They contain messenger RNA and macro non-
coding RNA, bioactive lipids, proteins, etc., which act as intercellular communication vehicles, with
the potential for transferring the receptor cells.
The reciprocal changes of intercellular
information take place between the stem cells, the undifferentiated cells and the adult ones, both in normal conditions and in pathological situations.
The human brain is by excellence the organ of
the mutual intercellular communication between its constituent neuroepithelial elements.
The multifunctional mesenchymal cell named
cordocyte which we had discovered lately is omnipresent at the level of the brain.
The information carrying microvesicles and
exosomes which are generated and released by the cordocytes have an extremely important and
complex role in the intercellular mediation.
We shall present further the imaging from the
samples we had analyzed.
The long arrows on the microscopic images
indicate the microvesicles, while the short arrows
reveal the exosomes.
The close communication between the
cordocyte and the smooth muscle cell within the wall of a cortical artery in a sample harvested from
a case with the thrombosis of the left internal
carotid artery had made the migrating cordocytic cell to get very close to the membrane of the
muscle cell. The cordocyte releases continuously
numerous microvesicles which are endocytosed by the smooth muscle cell.
At the periphery of the cerebral vascular walls
there are always cordocytic prolongations with microvesicles in the space between them which act
as homocellular information vesicles, or in the
vicinity of the marginal smooth muscle cells, as a mark for the heterocellular changes (Figure 17 a).
Although the microvesicles, which are
generated by the thousands, travel at a distance, they do not easily disintegrate.
They are released massively only at the level of
the target cells, and not in the unpopulated spaces.
Gradually, the non-endocytated vesicles disinter-
grate within the collagen mass. (Figure 17 b).
The number of the microvesicles which are
generated by the arachnoid cells is significantly
exceeded by the number of the microvesicular
bodies which release exosomes. However, a microvesicular body can contain numerous small
exosomes which disappear quickly from the
cellular landscape after the end of the action.
The cells also have another efficient mechanism
for the conservation of their products when they reach the extracellular space. Following the proper signals, they send cytoplasmic prolongations which
retain the vesicles with th eir adequate load in the
proximity of the cell membrane.
Consequently, the cell membrane has a very
important role in the vesicular circulation (Figure
17 c).
In Figure 17 d we can see how two arachnoid
cells, with very dense cytoplasm and with the nucleus rich in heterochromatin, are surrounded by a large number of microvesicles and by a
microvesicular body which contains exosomes.
Other arachnoid cells send cytoplasmic prolongations at whose ends there are released
microvesicles. Other vesicles, which had been
taken over from the extracellular space through endocytosis, give rise to a bidirectional flow.
Anyhow, the vesicular transfer is very intense at
the level of the arachnoid mater.
However, under the influence of certain
nocuous factors, the contents of the microvesicles and of the exosomes can change the phenotype of the cells in the respective microanatomical territory.
It is known that, through their contents of
messenger RNA and microRNA, the exosomes and the microvesicles contribute to the tumoral
development. Thus, we had ascertained that at the
periphery of a tumoral nodule located within the white matter there can be found both microvesicles
and exosomes (Figure 17 e).
We had also observed numerous microvesicles
and exosomes as intercellular information carrying
vehicles in the case of a fibrous meningioma
(Figure 17 f).

Leon Dănăilă 96

Figure 10. (a) A broken cortical vein show ing an undifferentiating cell (arrowed) and long cordocytes running towards the vascu lar
wall. (b) A broken cortical artery showing the mobilization of the precursor / stem cells and of the well-differentiated cordoc ytes in
front of a vascular rupture, while other mature cordocytes retain the isolated red blood cells ( OM 400).

Figure 11. A vascular wall defect with a fibrous thinned wall surrounded by cordocytes and by gliotic parenchyma.

The Cordocyte 97

Figure 12. A poorly structured venous wall in which the tunica me dia is lacking. Here we can se e a thick band containing collag en,
stem cells, mature cordocytes, which had surrounded numerous stem cells ( OM 200).

Figure 13. A broken cortical vein displayi ng a haemostatic platelet plug on the side with the broken and focally degenerated wa ll.
On the opposite side, we can see the proliferation of numerous stem cells in close contact with mature cordocytes (arrow)
(OM 200).

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Figure 14. Numerous cordocytes surrounding a cytoge netic focus near the va scular wall (arrows).

Figure 15. This image shows collateral neof ormation vessels (intermediate arrows), stem cells in re lation with cordocytes (shor t
arrows), cells in divisions (very long a rrows), and a double layer of mature cord ocytes disposed around the new vessels ( OM 400).

The Cordocyte 99

Figure 16. (a) Recent hemorrhagic focus delimitated by a thin and long cordocyte, which does not allow the red blood cells to e nter
into the cerebral substance. (b) In this image we can also observe the role of efficient anti-hematic barrier of the cordocyte, which is
hardly visible. Beyond it there are no red blood cells.

Leon Dănăilă 100

Figure 17. (a) Cordocytic prolongations with microvesicles in the space between them; (b) Non-endocytated vesicles within
the collagen mass which are in course of disintegration; (c) Cytoplasmic prolongations which capture the vesicles loaded
with exosomes located in the proximity of the cells. The important role of the cell membrane in the vesicular traffic; (d) Two
arachnoid cells surrounded by a large number of microvesicl es and a microvesicular body containing exosomes. The
arachnoid cells send cytoplasmic prolongations which releas e microvesicles. Other vesicles are taken over from the
extracellular space through endocytosis, fact which suggests the presence of the bidirectional flow; (e) The presence at the
periphery of a tumoral nodule (hemangiopericytoma) of both mic rovesicles and exosomes; (f) We can see numerous microvesicles
and exosomes surrounding the tumo ral cells of an meningioma.

The Cordocyte 101
In this way, with the help of the electron
microscopy, we had been able to identify the
presence of the extracellular vesicles generated by both the damaged cells, and by the necrotic tissue.
They make up an information transport system
which is indispensable for the cellular survival processes. In this context, the cordocyte is the
supervising cell of the human brain.
In conclusion, the cerebral intercellular
information transport is difficult to unravel. It
requires a good knowledge not only of its morphology, but also of the biochemical-
enzymatic equipment, of the chemoattracting
agents and of each RNA molecule which is specific for each cell.
The cordocytes and their most important cerebral
roles
According to the findings following our
histopathological and ultrastructural studies on the human brain in a variety of clinical conditions, it appears that these cordocytes might have the following important roles:
● A competitive role in the functioning of the
blood-brain barrier.
● A role in the repair and / or remodeling of the
broken or defective vascular wall (both arterial and venous).
● A role in vasculogenesis, especially in the
adult life, for the neoformation of collateral vessels in patients with thrombosis, with arteriovenous and venous malformations and in those with other injuries.
● A role of mechanical barrier in the periarterial
areas, especially in hypertensive humans.
● A role as an isolating barrier surrounding
certain infectious and hemorrhagic foci.
● An inhibitory role of the abnormal cells
proliferations into the subarachnoid space, suggesting their participation in the immune
surveillance, as a local defender against the
microtumoral development.
● A role in the possible compartmentalization
of the subarachnoid space and in the formation of channels around the cortical vessels for the drainage of the cerebrospinal fluid.
● The cordocytes in the human brain are
associated with information carrying extracellular vesicles.
● I am of the opinion that pia mater is a
cordocytic-vascular tissue with multiple roles in
the surveillance, the protection and the support of
the cerebral cortex. CONCLUSIONS
From the cerebral biopsies I had harvested
results that the cordocytes which I had discovered protect and control all the cerebral structures (the cerebral parenchyma, the blood vessels, the choroid plexus and the cerebral cortex) and that they lead a beneficial fight against all the
pathological processes.
Secondly, I am of the opinion that pia mater is a
cordocytic-vascular tissue with multiple roles in
the protection, the surveillance, and the preservation of the pericortical microenvironment.
With the help of pia mater, the cordocytes
influence the vasculogenesis, the reparation and the remodeling of the arteries and of the veins in conjunction with the stem cells.
The cordocytes, together with the stem cells and
with the undifferentiated cells, have an important
role in the vascular repair and remodeling through the extracellular vesicles which carry bidirectional information, while at the same time they inhibit the hematic, microtumoral and infectious invasion, as well as any aberrant cellular movement towards
the normal neural tissue.
The molecular and the biochemical-enzymatic
mechanisms of the referred to morphological
involvements remain unknown.
In the preservation of the plurifunctional
phenotypes there are also involved the adult cells and the differentiation processes of the mesenchymal stem cells, as well as those of the glial transdifferentiation around the perivascular nervous tissue.
Nevertheless, these similar phenotypes with
different cytogenetic origins are supported by the same molecular mechanisms.
The phenotype represents the sum of all the
characters which can be observed in an individual organism. They are determined by the genes, by
the dominance relationships between the alleles,
and by the interactions between the genes and the environment.
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