Current view of mesenchymal stem cells biology (brief review)
В настоящее время мезенхимальным стволовым клеткам (МСК) уделяется достаточно большое внимание, однако до сих пор не раскрытыми остаются некоторые аспекты их биологии. В обзоре представлены материалы современных исследований, посвященные проблемным вопросам биологии МСК. Кратко обсуждается возможнос...
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nasplib_isofts_kiev_ua-123456789-1568472025-02-23T18:06:05Z Current view of mesenchymal stem cells biology (brief review) Сучасні погляди на біологію мезенхімальних стовбурових клітин (короткий виклад) Современные взгляды на биологию мезенхимальных стволовых клеток (краткое изложение) Maslova, O.O. Reviews В настоящее время мезенхимальным стволовым клеткам (МСК) уделяется достаточно большое внимание, однако до сих пор не раскрытыми остаются некоторые аспекты их биологии. В обзоре представлены материалы современных исследований, посвященные проблемным вопросам биологии МСК. Кратко обсуждается возможность использования МСК в регенеративной медицине Ключевые слова: мезенхимальные стволовые клетки, регенеративная медицина, культивирование клеток. На сьогодні мезенхімальним стовбуровим клітинам (МСК) приділяють досить значну увагу, однак досі не розкритими залишаються деякі аспекти їхньої біології. В огляді представлено матеріали сучасних досліджень, присвячених проблемним питанням біології МСК. Коротко обговорюється можливість використання МСК у регенеративній медицині. Ключові слова: мезенхімальні стовбурові клітини, регенеративна медицина, культивування клітин. Although mesenchymal stem cells (MSC) are in a focus of attention, some aspects of their biology are still unclear. This paper is a review of current research on MSC biology. The use of MSC in regenerative medicine is also briefly discussed. Keywords: mesenchymal stem cells, regenerative medicine, cell cultivation. 2012 Article Current view of mesenchymal stem cells biology (brief review) / O.O. Maslova // Вiopolymers and Cell. — 2012. — Т. 28, № 3. — С. 190–198. — Бібліогр.: 91 назв. — англ., рос. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.00004C https://nasplib.isofts.kiev.ua/handle/123456789/156847 576.57.085.23.615.012 en Вiopolymers and Cell application/pdf application/pdf Інститут молекулярної біології і генетики НАН України |
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Reviews Reviews Maslova, O.O. Current view of mesenchymal stem cells biology (brief review) Вiopolymers and Cell |
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В настоящее время мезенхимальным стволовым клеткам (МСК) уделяется достаточно большое внимание, однако до сих пор не раскрытыми остаются некоторые аспекты их биологии. В обзоре представлены материалы современных исследований, посвященные проблемным вопросам биологии МСК. Кратко обсуждается возможность использования МСК в регенеративной медицине
Ключевые слова: мезенхимальные стволовые клетки, регенеративная медицина, культивирование клеток. |
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Article |
| author |
Maslova, O.O. |
| author_facet |
Maslova, O.O. |
| author_sort |
Maslova, O.O. |
| title |
Current view of mesenchymal stem cells biology (brief review) |
| title_short |
Current view of mesenchymal stem cells biology (brief review) |
| title_full |
Current view of mesenchymal stem cells biology (brief review) |
| title_fullStr |
Current view of mesenchymal stem cells biology (brief review) |
| title_full_unstemmed |
Current view of mesenchymal stem cells biology (brief review) |
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current view of mesenchymal stem cells biology (brief review) |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| publishDate |
2012 |
| topic_facet |
Reviews |
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https://nasplib.isofts.kiev.ua/handle/123456789/156847 |
| citation_txt |
Current view of mesenchymal stem cells biology (brief review) / O.O. Maslova // Вiopolymers and Cell. — 2012. — Т. 28, № 3. — С. 190–198. — Бібліогр.: 91 назв. — англ., рос. |
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Вiopolymers and Cell |
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2025-11-24T06:35:51Z |
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| fulltext |
UDC 576.57.085.23.615.012
Current view of mesenchymal stem cells biology
(brief review)
O. O. Maslova
Institute of Genetic and Regenerative Medicine, NAMS of Ukraine
67, Vyshgorodska Str., Kyiv, Ukraine, 04114
rotiferko@gmail.com
Although mesenchymal stem cells (MSC) are in a focus of attention, some aspects of their biology are still
unclear. This paper is a review of current research on MSC biology. The use of MSC in regenerative medicine is
also briefly discussed.
Keywords: mesenchymal stem cells, regenerative medicine, cell cultivation.
Mesenchymal stem (stromal) cells (MSC) are
considered to be the most promising instrument of cell
and tissue engineering. However, regardless of rather
long-term detailed study of MSC in the cell culture
there are still uninvestigated aspects of their biology.
As a main "white spot" may be considered the absence
of description of MSC properties in natural niches of
the organism and in artificially created cultivation con-
ditions. For instance, the author of [1] writes, "Mesen-
chymal stem cells (MSCs) have been well identified in
cultures obtained from various human tissues. How-
ever, they give no clue as to their native identity, fre-
quency, or anatomical location."
The objectivity of views on MSC is limited by the
differences in the data about MSC properties, possibly
acquired in artificial conditions of cultivation in labo-
ratories, and by the attempts to adjust these properties
to a specific set of phenotypic characteristics. The tra-
ditional definition of MSC as "clonogenic cells, capa-
ble of adhesing to plastic, expressing a specific set of
surface markers and differentiating trilinearly" is insuf-
ficient and requires clarification.
MSC properties depend on their origin from me-
senchyme – embryonic tissue, absent in the adult orga-
nism. Starlike cells of mesenchyme fill the cavities in
the embryo organism, synthesize the molecules of
intracellular matrix and thus support its architectonics.
They are capable of amoeboid motion and phagocytosis
[2]. The mesenchyme is formed during gastrulation. It
is most likely that this tissue originates from all three
germ layers [2–4]. This is what allows MSC of the adult
organism to transform into tissue cells of both meso-
dermal line and ento- and ectodermal origin [3, 4]. Loo-
se connective tissue is morphologically most close to
the mesenchyme in the adult organism, as it contains a
large amount of intercellular substance and fibroblasts.
Also primitive connective tissues are reticular tissue of
hematopoietic organs (bone marrow, spleen, etc.). The
intermediary state between embryonic mesenchyme
and adult connective tissue is taken by mucous con-
nective tissue of the umbilical cord matrix (Wharton's
jelly) (Fig.1) [5]. The phenomenon of reversible me-
senchymal and epithelial transitions (MET-EMT) is
observed both at a stage of organogenesis and during
postnatal (normal and pathological) morphogenetic
processes [6]. Such mutual transfers are characterized
by morphological changes in cells (Table). There is an
opinion that the of specificities of MET-EMT processes
will allow understanding the of MSC nature in vivo [7,
8].
190
ISSN 0233–7657. Biopolymers and Cell. 2012. Vol. 28. N 3. P. 190–198 Translated from Russian
� Institute of Molecular Biology and Genetics, NAS of Ukraine, 2012
Such transitions are most frequent during the for-
mation of spatial organization of organs in the embryo-
genesis [9]. In the mature organism MET and EMT are
remarkable for the processes of tissue regeneration as
well as for the formation of fibroses, carcinomas and
metastasis of tumors [10]. The transitions are regulated
by the different signaling cascades [7–10]. Micro-RNA
and post-translational modifications of proteins play a
significant role in the mentioned processes with the
impact of growth factors and cytokines [9].
Every year there appear new data on successful
isolation of MSC in accord classic criteria from rather
"exotic" sources, such as menstrual blood [11], teeth
[12] and peripheral blood [13, 14]. According to some
publications, MSC are present in the blood of healthy
people [15–17], according to others – they are either
absent [18] or appear only at some diseases or traumas,
requiring their systemic mobilization (for instance, at
severe burns) [19, 20]. It was shown that MSC from
peripheral blood have properties, analogous to MSC of
bone marrow [14]. However, the main attention is paid
to the cells, isolated from bone marrow, adipose tissue
and fetal tissues (placenta, umbilical cord, etc.) [21,
22]. Contrary to the adult organism, where the
mesenchyme is completely transformed to various
connective tissues, the umbilical cord as a derivative of
yolk sac and allantois contains a primitive form of ex-
traembryonic mesenchyme - Wharton's jelly [23]. Its
predominant part consists of fibroblast-like cells, acti-
vely synthesizing glycosaminoglycans. Some authors
believe that MSC obtained from the umbilical cord
matrix preserve not multipotent (like MSC of adults),
but pluripotent [24] potential (there are data on the
possibility of their expression of embryonic markers
Oct4 and Tra-1-60, Tra1-81, SSEA1, SSEA-4, [25]);
their immune phenotype somewhat differs from the
mature one which opens additional opportunities for
allotransplantations [26].
The first data on MSC were obtained in
1960–1970-s [27–31], but the issue of selecting a pro-
per name for them was actively raised only in
2004–2006. Intensification of the work with these cells
and expansion of sources of their isolation caused even
more frequent suggestions of substituting the term
"mesenchymal stem cells" with more precise definition,
which would accurately reflects biological specificities
of each population of these cells. The International
Society for Cell Therapy recommended the term
"multipotent stromal cells" [32]. However, nowadays
there is less interest to terminology, therefore, the terms
191
CURRENT VIEW OF MESENCHYMAL STEM CELLS BIOLOGY (BRIEF REVIEW)
Property Epithelial cells Mesenchymal cells
Cellular contacts
Adhesive contacts (via E-cadherin),
desmosome, tight junctions
Absent or weak
Cytoskeleton Cytokeratins Vimentin
Synthesis of extracellular matrix Laminin, collagen of type IV Fibronectin, collagens I/III
Expression of proteases Absent or weak High (metalloproteinases)
Morphofunctional differences between the cells of epithelial and mesenchymal type [9]
á âà
Fig.1 Comparison of the composition of mesenchyme and its derivatives (www.technion.ac.il/~mdcourse/): a – embryonic mesenchyme; b –
mucous tissue of the umbilical cord; c – loose connective tissue
192
MASLOVA O. O.
"mesenchymal stem cells" and "multipotent stromal
cells" are almost as frequent in modern literature. The
term "mesenchymal stem/stromal cells" also gained its
ground.
One of the main problems of MSC biology is that
all the places of their localization in the adult organism
in vivo have not been revealed yet [1, 33-35]. There are
only some data about the niches of MSC in the bone
marrow and perivascular sites, and it is shown that these
cells can be isolated from other tissues as well. The data
about MSC are related to in vitro systems [1, 33–36]
and one might assume that they have a considerably
modified receptor portrait due to the procedures of
isolation and reseeding [37–39]. Although MSC in the
culture are described in detail, nowadays there is
neither a specific marker nor even a clear-cut set of
markers to determine MSC in the organism. The active
search for the markers optimal combination for precise
identification is carried out. The International Society
for Cell Therapy made an attempt to present the MSC
properties according to the required criteria [32], but,
unfortunately, later they were proven to be insufficient
for complete characterization of MSC. According to the
recent recommendations of the International Society of
Cell Therapy, the properties, common for all the MSC
regardless of their origin and the method of isolation,
are as follows: a capability of adhesion to plastic (the
property, which may be observed even in the very cell
culture, not in the organism), easy differentiation into
chondro-, osteo-, and adipocytes, expression of CD105,
CD90, CD73 and no expression of CD34, CD45,
CD11, HLA-DR [32]. The list of other surface markers
has considerable variations, depending on the origin of
MSC. Among newly suggested positive markers are
CD13, CD29, CD271, CD166, CD146, 140b, CD106,
and others [40, 41]. There are combinations of dozens
and hundreds of surface markers, expressed by MSC,
but there is no clear-cut recommended set yet.
Some differences were also revealed in the poten-
tial of differentiating the subpopulations of MSC, iso-
lated from diversesources [35, 42].
Considerable difficulties are also related to the fact
that the abovementioned positive markers are rather
wide-spread among various cells of the organism. It
makes it impossible to distinguish MSC from the neigh-
boring cells, for instance, in tissue preparations. Thus,
CD105 (SH2), or endoglin, which is a glycoprotein,
included into the composition of the receptor complex
for TGF-beta, is expressed on the surface of endothelial
cells, activated macrophages, fibroblasts and cells of
smooth muscles [43], which makes it impossible to
distinguish MSC from these types of cells. Besides
MSC, CD90, or Thy-1, is also expressed on the surface
of thymocytes, neurons, hematopoietic stem cells,
NK-cells, endotheliocytes, renal cells, circulating
melanoma cells, follicular-dendrite cells, fibroblasts
and myofibroblasts [44]. The expression of CD73
(SH3/SH4), or ecto-5`-nucleotidase, is also remarkable
for oligodendrocytes, B- and T-lymphocytes, neurons,
perithelial cells, fibroblasts, cardiomyocytes and other
types of cells [45]. There is an opinion about the
suitability of these markers for the determination of
MSC in the cases, when the presence of other types of
cells is disregarded completely.
An assumption that the criteria for MSC deter-
mination in the culture may be related to other types of
cells is stated more and more frequently [1].
The most complicated is the MSC determination
right in the living organism [33–35, 46]. Despite suc-
cessful MSCisolation from different tissues, their natu-
ral niches are described in detail only for bone marrow
and perivascular regions [1, 39]. The fibroblast-like,
adhesive cells, capable of trilineardifferentiation and
corresponding to the phenotypic criteria of MSC, were
isolated from many tissues of the adult organism. Still,
it is yet to be revealed which morphofunctional pro-
perties in vivo are remarkable for these cells [1]. Recen-
tly there have been some reports on different types of
the adult organism, which might be capable of acquir-
ing the properties of MSC in the culture [1, 35]. These
cells allegedly include perithelial cells, fibroblasts,
myofibroblasts, reticular cells, intestinal cells and some
others [47]. Most articles are devoted to fibroblasts [1,
35, 48, 49], as immediate derivatives of the mesen-
chyme, and to perithelial cells [1, 50] as the cells, inha-
biting one of alleged niches of MSC. There is an as-
sumption that these cells are in different functional
states, including multipotent one. It is also probable that
a definite (very small) amount of embryonic mesen-
chymal cells does not reach the final stages of dif-
ferentiation and remains in the stem state as a rege-
nerative pool. According to current views, MSC are a
heterogeneous group of cells with stem properties [1,
35, 51]. It is considered that for better understanding of
MSC state in vivo it is required thorough study of the
chemical and cellular composition of MSC niches
(which is currently worked on in the prominent labo-
ratories of the world) as well as detailed elaboration of
the notions of the functional and structural role of MSC
in health and disease.
Being in the natural environment inside the orga-
nism, MSC interact both with molecules of the extra-
cellular matrix and with each other as well as with other
types of cells. According to the current data, the extra-
cellular matrix is not only a mechanical support, but
also a combination of ligands, launching definite signa-
ling pathways via specific receptors [52]. The fate of
MSC considerably depends on the matrix properties.
The critical importance is attributed to both the nature
of substances, surrounding the cells, and their physical
characteristics, such as rigidity and flexibility (recent
investigations prove that in some conditions the change
in density and solidity of the substrate may play a key
role in the selection of a way of MSC differentiation)
[53–55].
Cell isolation from any tissue destructs (mechani-
cally or enzymatically) both intercellular matrix and in-
tercellular connections, thus causing considerable cha-
nges in the receptor portrait [37, 38] on the surface of the
isolated cells. This phenomenon may be called "re-
ceptor shock" (Fig.2) which eliminates all the possi-
bilities of cultivating native MSC. It is only after this
serious restructuring in conditions of the culture of cells,
which do not reproduce the composition of natural
niches of the organism, that the cultivated material
acquires the properties, described in vitro (Fig.3). The-
se features help identifying MSC according to the known
properties, but one should realize that they may differ
from the properties of MSC, inherent to the organism.
None of the current approaches to the optimization of
cultivation conditions, in particular, an application of
artificial or natural materials or bioreactors, allow
accurate and precise reproduction of in vivo conditions.
The multi-level regulation of the nervous, humoral, and
immune activity of all cells in the organism is the least
reproducible. Thus, summing up the abovementioned
one may conclude that MSC is the name for the cells,
acquiring a certain phenotype outside of the organism.
One of vital issues is the possibility of long-term
cultivation of MSC. According to the recent literature
data, MSC are irreversibly modified with each
consequent passage [37, 56, 38]. However, there are
different opinions as to the passage of MSC cultivation
without any loss of multipotency [57]. Some authors
indicate feasible morphophysiological modifications of
the cells and disorders of the expression of certain
genes as early as at the stage of 2nd–3rd passages [58],
others – at the 5th– 6th passage [59]. The analysis of these
data allows the conclusion about the absence of
standardized methods of sustaining cells in the stable
multipotent state.
The cultivated cells may be introduced into the ex-
perimental organism with different purposes. Partial
evaluation of the efficiency of introduction of the cel-
lular material requires tracking the ways of its mig-
ration. The modern methods of detecting the introduced
MSC are as follows: PCR (RT-PCR), which allows de-
termining the availability of Alu-sequences, specific
for humans, and other markers in the animal organs,
which were introduced with human MSC; staining with
fluorescent proteins (with subsequent analysis of his-
tological preparations or with the method of confocal
microscopy in vivo) and labeling with radioactive
193
CURRENT VIEW OF MESENCHYMAL STEM CELLS BIOLOGY (BRIEF REVIEW)
Fig.2 Schematic presentation of some cell modifications during
obtaining the culture
particles; PET technology (positron emission tomo-
graphy), magnetic resonance investigations [60–62].
According to the literature data, describing the distri-
bution of MSC, systemically introduced into organisms
of experimental animals from different sources, the
cells are firstly detected in the lungs (approximately 70
%), later they may be tracked in the liver (up to 15 %),
kidneys (up to 20 %), spleen, heart and blood flow [62].
The data about the presence of the introduced MSC in
the bone marrow are ambiguous. Some authors demon-
strate the presence of exogenous MSC in the bone mar-
row [63], while others do not observed this phenome-
non [64]. Up till now there is no univocal answer to the
question, whether MSC are capable of self-destruction
after the excretion of specific substances, whether they
are transformed into the types of cells, necessary for the
damaged organ, or undergo no modifications.
Various approaches in vivo allow understanding
the specificities of homing and distribution of
introduced cells. However, taking into consideration
the potential modifications, inherent to pre-cultivated
material, it is difficult to determine the MSC
localization in tissue and organs [1, 65]. Therefore, one
of urgent tasks is the search for difference in the states
of cells following the scheme: presence in a niche –
isolation from the tissue – cultivation – introduction
into the organism – formation of a new niche on request
(with subsequent differentiation or self-destruction
after the release of paracrine factors, etc.)
Regardless of the mentioned difficulties, the
cultivated MSC are already used in regenerative
therapy [64–67]. There are attempts to decrease the
impact of cultivation on MSC metabolism and to
preserve their original characteristics. The xenogenic,
allogenic, and autologous variants of MSC application
were tested in experiments on animals. Human MSC
are also actively introduced in clinical practice. The
issue of clinical application of MSC from various
sources has been highlighted in a number of extensive
reviews [68–73], therefore, this work will only present
a brief outline of the main approaches in regenerative
medicine, where the application of MSC is required.
There are several works, where cellular material was
used in the phases 1– 3 of clinical trial [74, 75],
however, the results are rather ambiguous. The stages 1
and 2 were rather successful in the most cases, but there
was some disagreement about the stage 3, concerning
suitability of application of MSC compared to
traditional medical preparations. The review, cited in
[76], is devoted to the discussion of this issue.
The cells, cultivated in vitro, may be introduced to
the patient either locally (as, for instance, in case of
treating joints or repairing wounds) or systemically (in
particular, for the myocardial infarction). Systemic
introduction requires the application of a suspension or
cellular aggregates of minimal size in order to eliminate
the risk of embolism. The application of MSC as
carriers of certain substances (the most wide-spread
among them being antitumor preparations) seems to be
more and more probable [77]. The MSC with in-built
genetic constructions acquire the capability of
synthesizing and releasing the required substances [46,
77]. The problems, occurring in the course of applying
MSC in regenerative medicine, are as follows: selection
of optimal sources, cultivation without loss of stem
characteristics, selection of an adequate method of
introduction into the organism, possibility of tracking
the fate of introduced material in the organism.
Although the clinical aspects are not reviewed in
this work in detail, it is noteworthy to indicate the
fields, where this material may be used, and to discuss
shortly the reasons of MSC application. According to
the literature data, the pathologies, which may be
treated using MSC, include neurodegenerative [78] and
autoimmune diseases [79, 80], cardiovascular diseases
[81], strokes [82], diseases of locomotor system [83],
traumas [84], tumors, including sarcomas [85]. The
194
MASLOVA O. O.
Fig.3 MSC culture, isolated from the matrix of human umbilical cord,
passage 1, unstained; x100
application of MSC in the clinical practice is related to
their potential impact on the immune response [86], to
the expressed paracrine effects (for instance, release of
growth factors and cytokines) [68], and participation in
the restoration of damaged tissues [87]. A number of
modern studies indicate a considerably important role
of paracrine effects of MSC introduction. Due to the
capability of MSC to secrete growth factors, cytokines,
and chemokines they may regulate the state of
microenvironment and thus stimulate the regeneration
of tissues. Numerous works are devoted also to the
immunomodulating effects of MSC , in particular, their
impact on various stages of the immune response was
demonstrated in[88–91].
The analysis of current views on MSC biology
allows the following conclusions:
– specific anatomic localization of MSC in the adult
organism is determined only for the bone marrow,
although these cells were detected in other tissues as
well;
– up to now there is no definite formulation of a
concept about MSC natural niches ;
– the procedures of MSC cultivation outside of the
organism result in the changes in the receptor portrait
and other characteristics of MSC, which does not
permit precise evaluation of their properties;
– it still remains vague an issue of selecting
maximally exhaustive markers, distinguishing MSC
from other cells with similar phenotypic properties and
allowing to demonstrate the MSC pool in different
tissues.
More accurate definition may be proposed: MSC in
culture is a heterogeneous group of multipotent cells,
which are likely to acquire certain phenotypic
properties after the isolation from different tissues: the
expression of a set of surface markers, adhesion to
plastic, capability of induced differentiation.
Thus, the understanding of cytological and
biochemical specificities of MSC not only in culture,
but also in living organism, is a key issue, the solution
of which is required for their more efficient and safe
application in clinical practice. Current works, directed
towards the preparation of MSC for their application in
regenerative medicine, should be aimed at decreasing
the consequences of cell cultivation and search for the
ways of their long-term sustaining in the culture
without any modifications.
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ùåííûå ïðîáëåìíûì âîïðîñàì áèîëîãèè ÌÑÊ. Êðàòêî
îáñóæäàåòñÿ âîçìîæíîñòü èñïîëüçîâàíèÿ ÌÑÊ â ðåãåíåðàòèâ-
íîé ìåäèöèíå
Êëþ÷åâûå ñëîâà: ìåçåíõèìàëüíûå ñòâîëîâûå êëåòêè, ðåãå-
íåðàòèâíàÿ ìåäèöèíà, êóëüòèâèðîâàíèå êëåòîê
Î. Î. Ìàñëîâà
Ñó÷àñí³ ïîãëÿäè íà á³îëîã³þ ìåçåíõ³ìàëüíèõ ñòîâáóðîâèõ êë³òèí
(êîðîòêèé âèêëàä)
Íà ñüîãîäí³ ìåçåíõ³ìàëüíèì ñòîâáóðîâèì êë³òèíàì (ÌÑÊ) ïðè-
ä³ëÿþòü äîñèòü çíà÷íó óâàãó, îäíàê äîñ³ íå ðîçêðèòèìè çàëèøà-
þòüñÿ äåÿê³ àñïåêòè ¿õíüî¿ á³îëî㳿.  îãëÿä³ ïðåäñòàâëåíî ìà-
òåð³àëè ñó÷àñíèõ äîñë³äæåíü, ïðèñâÿ÷åíèõ ïðîáëåìíèì ïèòàí-
íÿì á³îëî㳿 ÌÑÊ. Êîðîòêî îáãîâîðþºòüñÿ ìîæëèâ³ñòü âèêîðè-
ñòàííÿ ÌÑÊ ó ðåãåíåðàòèâí³é ìåäèöèí³.
Êëþ÷îâ³ ñëîâà: ìåçåíõ³ìàëüí³ ñòîâáóðîâ³ êë³òèíè, ðåãåíåðà-
òèâíà ìåäèöèíà,êóëüòèâóâàííÿ êë³òèí.
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Received 11.11.11
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