IMMUNOLOGY IN SERBIA

The potential of interleukin-17 to mediatehematopoietic response

Aleksandra Krstic • Slavko Mojsilovic • Gordana Jovcic •

Diana Bugarski

Published online: 4 March 2012

� Springer Science+Business Media, LLC 2012

Abstract It has long been known that T cells have the potential to modulate hematopoietic response in different ways.

More recently, the importance of interleukin (IL)-17-secreting Th17 cells in T-cell-mediated regulation of hematopoiesis

was indicated by the line of evidence that IL-17 links T-cell function and hematopoiesis through stimulation of granu-

lopoiesis and neutrophil trafficking. Furthermore, our data demonstrated that IL-17 also affects other cells of hematopoietic

system, such as erythroid progenitors, as well as mesenchymal stem cells. In order to better understand the regulatory role

of IL-17 in hematopoiesis, molecular mechanisms underlying the effects of IL-17 on hematopoietic and mesenchymal stem

cells were also studied.

Keywords IL-17 � Hematopoiesis � Myeloid and erythroid progenitors � Bone marrow � Spleen

T cells in regulation of hematopoiesis

Hematopoiesis occurs throughout the lifetime of an

organism to regularly replenish the different cellular

components of the blood. This dynamic process is ulti-

mately supported by the hematopoietic stem cells, since

they have the ability to differentiate into each member of

every blood lineage, as well as the capacity to self-renew,

thus maintaining a population of undifferentiated, imma-

ture stem cells. These intriguing features of hematopoiesis

have fueled extensive investigation of the mechanisms

governing lineage commitment and maintenance of

hematopoietic stem cells in adult bone marrow over the last

several decades. Nowadays, it is known that a large part of

hematopoiesis control depends on the bone marrow

microenvironment, where a complex network of various

cell types regulates hematopoiesis through cytokine

secretion and cell-to-cell and cell-to-matrix interactions.

The involvement of the immune system in regulation of

hematopoiesis was suggested during 1970s of the last

century by several investigators including those from our

laboratory. Namely, in the experiments using the murine

thymectomy model, the important role of thymus and T

lymphocytes was demonstrated by the facts that the thy-

mectomized mice were anemic, had arrested erythroid

maturation, and reduced number of spleen colony-forming

units in the bone marrow and spleen, while intravenous

injection of thymocytes in sublethally irradiated mice

stimulated hematopoietic reconstitution [1–6]. All of these

studies pointed to the cooperation between hematopoietic

cells and T cells for the maintenance of optimal hemato-

poiesis in mice. Further research has demonstrated that

thymus-derived T lymphocytes can produce cytokines that

have powerful effects on hematopoiesis. Experiments

performed in the 1980s using in vitro culture systems

suggested that T cells might regulate hematopoietic

progenitor cell activity through production of GM-CSF

(granulocyte–macrophage colony-stimulating factor), M-CSF

(macrophage colony-stimulating factor), interleukin-3

(IL-3), and IL-4 [7–11]. These cytokines act on hemato-

poiesis through both direct and indirect mechanisms at

several developmental stages, including the regulation of

A. Krstic � S. Mojsilovic � G. Jovcic � D. Bugarski (&)

Laboratory for Experimental Hematology and Stem Cells,

Institute for Medical Research, University of Belgrade,

Dr Subotica 4, P.O. Box 102, 11129 Belgrade, Beograd, Serbia

e-mail: dianab@imi.bg.ac.rs

Diana Bugarski

123

Immunol Res (2012) 52:34–41

DOI 10.1007/s12026-012-8276-8

hematopoietic stem cells, hematopoietic progenitor cells,

and mature cells in the peripheral blood. More recent

research showed that T cells regulate hematopoiesis

through secretion of various other cytokines, such as IL-5,

IL-6, IL-9, IL-13, IFN-c, TNF-a, TGF-b, oncostatin M

(OSM), as well as through a large number of different

chemokines that also have powerful effects on hemato-

poiesis [12–17]. Despite these facts, the exact role of T

cells as source of cytokines involved in regulation of

hematopoiesis has been difficult to study, since most

hematopoietic regulatory cytokines are also produced by

other cell types besides T cells. Another difficulty for the

research of T-cell-regulated hematopoiesis is the complex

interplay of the numerous different factors produced by T

cells, which can either promote or suppress the hemato-

poietic cell growth and differentiation. Accordingly, both

the influence of T-cell-derived cytokines on hematopoiesis

and the subsequent integration of sometimes conflicting

signals by the hematopoietic cells are poorly understood.

The essential role of T cells in stimulation of hematopoiesis

during infection, as well as during the hematopoietic

recovery after bone marrow transplantation, has been

clearly demonstrated; however, the T-cell activity in

maintenance of normal hematopoiesis is still poorly

investigated. Recent findings gave important evidence that

CD4? cells might represent the key regulators of what we

currently understand as normal hematopoiesis. Namely,

normal blood cell production was believed to be the result

of an basal, ‘‘innate’’, hematopoietic activity, while an

‘‘adaptive’’ hematopoietic state develops in response to

stress-induced stimulation (infection, inflammation), thus

providing specific lineage amplification depending on the

nature of the stimuli. However, recent data showed that

constant antigenic stimulation of bone marrow CD4 ? T

cells is essential for the maintenance of normal hemato-

poiesis and unveiled their role as hematopoiesis amplifiers

of innate immune response, thus assuring suitable levels of

defense [18].

Understanding how T cells regulate both steady-state

hematopoiesis and induced hematopoiesis during an

immune response is critically important for increasing our

knowledge of both hematopoietic control and immune

regulation. The potential of the specific T helper cell sub-

sets, Th1 and Th2 cells, to modulate the hematopoietic

response in different ways, although not well characterized,

has been demonstrated and reported [19]. However,

defining the role of newly recognized subset of IL-17-

secreting T cells, Th17 cells, as well as the regulatory T

cells (T-regs), in regulation of hematopoiesis is still in its

infancy. Only recent data implied to the presence of T-regs

in hematolymphoid compartments and demonstrated the

ability of T-regs to modulate hematopoietic progenitor

cells activity, suggesting that T-regs are not restricted in

their regulatory actions within the adaptive and innate

immune systems [20]. As for the IL-17, even the early

studies pointed to this cytokine as an example of bridging

between T-cell function and haematopoiesis, demonstrat-

ing that IL-17 induces production of various pro-inflam-

matory cytokines, but also those with haematopoietic

effects, such as GM-CSF, G-CSF (granulocyte-colony-sti-

mulating factor), and IL-6 [21]. As the understanding of its

function improved, it was shown that IL-17 is at the heart

of a regulatory circuit controlling neutrophil homeostasis,

while studies of our group and some others demonstrated

that IL-17 also affects other cells of hematopoietic system,

such as erythroid progenitors, as well as mesenchymal stem

cells (reviewed in detail in further text). These findings

focused our research on molecular mechanisms underlying

the effects of IL-17 on hematopoietic and mesenchymal

stem cells in order to better understand the regulatory role

of IL-17 in hematopoiesis, both during the normal, steady-

state hematopoiesis and disturbed, altered hematopoietic

responses.

Effects of IL-17 on hematopoietic cells

Initial evidence of IL-17’s stimulatory effect on myeloid

cells was obtained after in vitro experiments which dem-

onstrated that IL-17 can induce the proliferation of

CD34 ? human stem cells, as well as their maturation into

neutrophils, only when cocultured with fibroblasts [16].

This way it was suggested that IL-17 affects hematopoietic

stem cells indirectly, through the induction of fibroblasts to

release secondary cytokines with hematopoietic effects,

including G-CSF and IL-6. Further on, the in vivo

expression of IL-17 in an experimental model of adeno-

virus-mediated gene transfer of the murine IL-17 cDNA

induced a profound stimulation of both bone marrow and

splenic granulopoiesis and led to expansion of myeloid

hematopoietic stem and progenitor cells (high proliferative

potential colonies—HPPC, colony-forming-unit–granulo-

cyte-erythrocyte-megakaryocyte-monocyte—CFU-GEMM,

and colony-forming-unit-granulocyte–macrophage—CFU-

GM) and neutrophilia, in part through release of second-

ary cytokines, such as G-CSF [22]. Data obtained in the

same experimental model also showed that for optimal

granulopoiesis, beside G-CSF release, IL-17-mediated

effects require the presence or induction of the trans-

membrane form of stem cell factor [23] and confirmed

that IL-17 stimulates the production and differentiation of

granulocyte lineage cells by inducing secondary hemato-

poietic cytokines [24]. Our data, obtained in a different

experimental approach, demonstrated that even a single

injection of IL-17 recombinant protein elicits a cascade

of biological changes in vivo, affecting the cells of

Immunology in Serbia (2012) 52:34–41 35

123

granulocytic lineage, as well as the levels of cytokines

released, primarily IL-6, in both murine bone marrow and

spleen [25–27]. The most obvious in vivo response of

granulocytic cells to IL-17 administration was observed at

the level of bone marrow morphologically recognizable

proliferative granulocytes and spleen metamyelocytes,

indicating that more mature progenitors respond first to its

action. Consistent with these findings were our results

obtained in the analysis of the effects of IL-17 on the

mature granulocytes, since IL-17 did not provoke any

significant changes in different functional activities of the

peripheral blood granulocytes from normal subjects,

therefore suggesting that IL-17 may not express its pro-

inflammatory ability in steady state, when the requirement

for its action does really not exist [28]. In our later

research, by evaluating the hematological consequences of

multiple applications of IL-17, we confirmed that IL-17

stimulates the increase in net hematopoiesis in normal

mice, inducing significant stimulation of the hematopoietic

progenitors in the bone marrow and spleen, but with more

robust activity seen on the expansion of splenic precursor

cells [29]. Namely, the stimulation of myeloid CFU-

GEMM progenitor cells was observed in both hemato-

poietic organs, while a significant increase in CFU-GM

progenitor cells was observed only in the spleen. These

changes were accompanied with significantly increased

numbers of total granulocytes in both organs.

The role of IL-17 in erythropoiesis has not been as

extensively studied as its role in granulopoiesis. Our first

studies have shown that IL-17, besides the influence on

granulocytic cells, also affects, both in vitro and in vivo, the

cells of erythroid lineage, by stimulating development of

early erythroid progenitors, burst-forming-unit-erythroid

(BFU-E), but inhibiting the growth of late-stage erythroid

progenitors, colony-forming-unit-erythroid (CFU-E), from

normal murine bone marrow [26, 27]. However, our further

studies demonstrated that hematopoietic effects of IL-17

were highly dependent on the microenvironment, since the

effects on the erythroid compartments in mouse spleen were

opposite to those observed in the bone marrow. The dif-

ferences were attributed to different cytokine profiles

induced by IL-17 related to the tissue microenvironment in

which hematopoiesis occurs [25]. The experiments per-

formed with multiple in vivo applications of IL-17 con-

firmed that the most profound effects of IL-17 can be

observed within the erythropoiesis, since IL-17 induced

significant alterations in the frequency of erythroid progen-

itor cells in both bone marrow and spleen, by stimulating

BFU-E and suppressing the CFU-E. These alterations were

accompanied with more than an eightfold increase in

peripheral blood CFU-E numbers in mice treated with IL-17,

indicating that IL-17 led to mobilization of erythroid pro-

genitors to the peripheral blood. As a consequence of the

changes within the erythroid cell compartments, significant

reticulocytosis was observed, which evidenced that effective

erythropoiesis occurred [29]. Similarly, as seen within the

myeloid cells, the most obvious in vivo response of ery-

throid cells to IL-17 administration was observed at the level

of the late-stage erythroid progenitors CFU-E, confirming

that more mature hematopoietic progenitors respond first to

its action.

Investigating the mechanisms underlying IL-17 effects on

erythroid cells, our data provide evidence that the stimulatory

effects of IL-17 on the BFU-E production, both on murine

bone marrow cells and human CD34 ? cells, are predomi-

nantly indirect, via secondarily induced cytokines, such as

IL-6 and erythropoietin (EPO) [26, 30]. We also demon-

strated that at least part of the effect related to the inhibition of

CFU-E is mediated by nitric oxide (NO) production [31],

through activation of both inducible nitric oxide synthase

(NOS) and constitutive, endothelial NOS isoforms, as well as

the activation of p38 mitogen-activated protein kinase (MAPK)

[32]. The mutual link between IL-17 and NO in the process of

hematopoiesis was also tested in vivo, and the results confirmed

the specific role of NO only in the IL-17-reducing effect on

bone marrow CFU-E [29]. More recent results indicated

that, beside p38 MAPK, MEK1/2-ERK1/2 MAPK signal-

ing is also involved in IL-17-induced CFU-E inhibition,

while JNK and/or MEK1/2-ERK1/2 MAPKs activation

underlies the IL-17-induced stimulation of BFU-E growth

(unpublished data). Furthermore, we demonstrated that

IL-17 enhances the expression level of erythroid-specific

factor GATA-1 in murine bone marrow cells (unpublished

data), which in light of previous reports that GATA-1

overexpression inhibits erythroid differentiation could be

related to IL-17-mediated inhibition of CFU-E growth [33, 34].

Beside the influence of IL-17 during steady-state

hematopoiesis, its effects on hematopoietic cells during the

state of disturbed or altered hematopoiesis were also ana-

lyzed, although not in many cases. Our initial in vitro

studies [27] performed on the bone marrow cells obtained

from sublethally irradiated mice demonstrated that the

effects of IL-17 were lineage-dependent, as well as

dependent on hematopoietic progenitor cells’ stage of dif-

ferentiation and the time after the irradiation. These com-

plex changes were accompanied by IL-17-induced

augmented release of IL-1a, IL-6, and EPO by irradiated

cells, thus suggesting that the extent of IL-17 involvement

is dependent on the physiological status of the organism,

that is, on the differential host requirements for regulatory

molecules. Moreover, in the case of IL-6 secretion, stim-

ulatory effect of IL-17 was also dependent on the different

endogenous cytokine levels occurring on various days after

irradiation, indicating a role of IL-17 in a fine-tuned reg-

ulation of the cytokine production. Later data from other

groups showed that following sublethal radiation-induced

36 Immunology in Serbia (2012) 52:34–41

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myelosuppression, in vivo overexpression of murine IL-17

substantially enhances granulopoietic restoration, charac-

terized by increase in neutrophils, as well as both splenic

and bone marrow progenitor cells [35]. Our data obtained

during the naturally acquired Syphacia obvelata infection

in mice confirmed that the activity of IL-17 differs

depending on physiological/pathological status of the

organism. Namely, we demonstrated that this pinworm

parasite induces significant hematopoietic changes during

infection, characterized by increased myelopoiesis and

erythropoiesis in infected animals. This stimulation of

hematopoiesis was accompanied by altered sensitivity of

the bone marrow myeloid and erythroid progenitors from

infected mice to IL-17, as compared to non-infected con-

trols, and the changes in reactivity were manifested both at

the cellular and molecular level [36, 37].

Effects of IL-17 on mesenchymal stem cells

The idea that T cells act through the bone marrow stromal

cells to support hematopoiesis came with the reports that

bone marrow grafts depleted in T cells lead to delayed or

failed engraftment [38, 39]. Bone marrow stromal cells are

known to provide microenvironmental support for hema-

topoietic stem cells through the secretion of growth factors

and cytokines, but also through direct contact in cell–cell

interactions and through production of extracellular matrix

[40, 41]. All the stromal cells in bone marrow, except

macrophages, originate from pluripotent bone marrow

mesenchymal stem cell (BM-MSCs) that exhibit ability

to self-renew as well as to differentiate into cells of

mesodermal lineage, including osteocytes, adipocytes,

chondrocytes, myocytes, tenocytes, myocardiocytes, and

hematopoietic supportive stroma [42–44]. Thus, it is not

surprise that bone marrow stromal cells are also believed to

be the main target for IL-17 in its action on hematopoietic

cells. Even in the first reports, IL-17 was presented as a

cytokine that achieves its effects primarily by acting on

different stromal cells (fibroblasts, osteoblasts, chondro-

cytes, bone marrow stromal cells…), stimulating them to

secrete other soluble and membrane-bound factors, among

which are IL-6, G-SCF, GM-CSF, SCF, and NO [16, 21,

23, 45–49]. IL-17 also induces many genes in stromal cells,

including those implicated in hematopoiesis, such as IL-6

gene and its transcriptional regulators (C/EPB family,

IjBf), different CC and CXC chemokines, and apoptosis-

related proteins, such as FAS and Lipocalin 2 [50, 51]. The

particularly high levels of IL-17RA (IL-17 receptor A)

expression on stromal cells, including bone marrow mes-

enchymal stem cells, are in line with this notion [16, 52–

54]. However, only recently, IL-17 was shown to act as

potent growth factor for both murine and human BM-

MSCs, affecting their proliferation and differentiation

potential. The results of our group and the others revealed

that IL-17 increases the frequency and the average size of

CFU-F (colony-forming-units-fibroblast) derived from

murine and human bone marrow, as well as the prolifera-

tion of murine BM-MSCs in a dose-dependent manner [52,

53, 55]. The effect on MSCs proliferation was also shown

to be dependent on the generation of reactive oxygen

species (ROS) and activation of MEK-ERK kinase path-

ways [53], while in our experiments, for its activity on

murine BM-MSCs proliferation, IL-17 utilized both p38

and ERK MAPKs [52].

As regarding the influence of IL-17 on the MSCs dif-

ferentiation, the reported results are diverse, and it appears

that the effects of IL-17 are highly dependent on the spe-

cific microenvironment and/or specific host organism

requirements. Namely, IL-17 was shown to enhance the

osteogenic differentiation of human MSCs [53], to inhibit

adipogenesis in human MSCs by promoting lipolysis of

differentiated adipocytes [56], but also to enhance adipo-

genic differentiation in mouse multipotent MSCs [57]. The

data from our group indicated that IL-17 did not interfere

with the murine BM-MSCs differentiation toward osteo-

blasts or adipocytes [52]. However, to evaluate the effects

and associated mechanisms of IL-17 on mesenchymal

multilineage commitment, we also analyzed the influence

of IL-17 on mouse C2C12 cell line, since these myoblast

progenitor cells originating from undifferentiated mesen-

chymal cells have the capacity to differentiate in vitro into

myogenic and osteogenic lineages. The results obtained

showed that IL-17 inhibits myogenic, but induces the

osteogenic differentiation of C2C12 cells, and both through

ERK1,2 MAPK-dependent mechanism [58], therefore

indicating its potential to modulate mesenchymal cell

balance by switching their commitment from myogenic to

osteogenic lineage by activation of ERK1,2 MAPK. The

data concerning the effects on mesenchymal stem cells and

their multilineage differentiation potential are just begin-

ning to unravel its novel functions, and further studies

should address this issue in more detail.

The role of IL-17 in regulation of hematopoiesis

The IL-17 is emerging as critical player in inflammatory

diseases and host defense responses to extracellular bac-

teria and fungi, acting largely by inducing neutrophil

recruitment [59–62]. It is well established that IL-17 as a

response cytokine released within the microenvironment of

infections is required for mounting adequate immune

responses in both innate and adaptive immunity. Sub-

stantial data supported that the neutrophil homeostasis and

trafficking to tissues are regulated by the IL-23/IL-17/G-

Immunology in Serbia (2012) 52:34–41 37

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CSF–cytokine-controlled loop. Neutrophil turnover has

been shown to play an important role in the homeostatic

regulation of IL-17 and its control of granulopoiesis [63].

When neutrophil migration into tissues is blocked by

adhesion molecule deficiency, macrophages and dendritic

cells secrete excessive levels of IL-23, a key cytokine that

drives Th17 development and IL-17 production [64, 65],

leading to increased G-CSF-dependent granulopoiesis.

Neutrophil phagocytosis by macrophages and dendritic

cells suppresses their production of IL-23, thus decreasing

IL-17 synthesis and G-CSF-dependent granulopoiesis [63].

Therefore, IL-17 regulates granulopoiesis by its control of

G-CSF expression, while circulating neutrophils act in a

negative feedback loop to block excessive production of

Th17 cells and IL-17. In Th17-mediated pathologic

inflammation, the neutrophil response elicited by IL-17-

dependent regulation plays a role in the initiation, but also

in the maintenance of inflammation. Moreover, it was

shown that IL-17 cooperates synergistically with various

inflammatory cytokines, such as TNF-a, IL-1b, and inter-

feron-c, augmenting the induction of pro-inflammatory

responses from various target cells [66], thus placing this

cytokine in the midst of a complex network that amplifies

inflammation.

Regarding the regulation of erythropoiesis, the role of

IL-17 is not so obvious. The erythropoietic effects were

highly dependent on the hematopoietic microenvironment

and secondary induced ambient regulators [25, 26], which

raises the possibility that if IL-17 is capable to mediate

hematopoiesis both via NO induction in bone marrow as

well as by NO-independent effect in spleen, then not only

its mode of action but its role in the medullar and splenic

hematopoiesis/erythropoiesis could also be different. Thus,

the opposite effects exerted on mature hematopoietic pro-

genitors in the bone marrow, that is, stimulation of pro-

liferative granulocytes and inhibition of CFU-E, imply that

IL-17 may be one of the key cytokines that coordinate and

control hematopoiesis, as in this way IL-17 can enable the

switch in cell production from the erythroid to the granu-

locyte lineage during inflammation or infection when

enhanced defenses are required. In line with this proposed

homeostatic role of IL-17 [31, 32] are studies performed in

IL-17 receptor-knockout mouse pointing to IL-17 as an

acute response cytokine, rather than being cytokine

required for baseline homeostasis of the hematopoietic

system [35]. However, in the same time, the stimulatory

effect on splenic erythropoiesis in mice could not be

neglected, since the spleen is an active hematopoietic organ

in rodents, and the splenic hematopoietic microenviron-

ment in vivo predominantly supports the differentiation of

hematopoietic progenitors into erythroid lineage Therefore,

the enhanced synergy of IL-17 with other cytokines already

present at basal levels in the spleen might be sufficient to

induce the augmented bioactivity on erythropoiesis.

Important, but still not well characterized, role of IL-17

is its potential to affect mobilization of hematopoietic stem

cells. In the model of IL-17 overexpression with recom-

binant adenovirus technology, mobilizing effects of IL-17

on hematopoietic precursor cells (CFU-GEMM and

HPPC), as well as primitive hematopoietic stem cells, that

is, stem cells with both short- and long-term reconstituting

capacity, were demonstrated for the first time in mice [67].

In our experimental approach, multiple applications of IL-

17 recombinant protein led to significant mobilization only

of erythroid progenitors to the peripheral blood, raising a

question of the biological significance of this effect [29].

At this moment, we can only speculate what is the physi-

ological impact of such mobilization, but there are

increasing evidence that the recruitment of hematopoietic

stem/progenitor cells from the bone marrow into peripheral

blood is also a physiological phenomenon important for the

protection of these cells from toxic injury, a homeostatic

mechanism involved in the maintenance of a fixed number

of hematopoietic stem/progenitor cells in the bone marrow,

and/or a response to stress signals during injury and

inflammation as a part of the host’s immune system

defense response [68]. We have previously proposed a

hypothesis that IL-17 is the part of a regulatory cytokine

network involved in bone marrow homeostatic mecha-

nisms. Additionally, IL-17 is a cytokine that has a pro-

inflammatory role and has been implicated in either the

causation or progression of many inflammatory conditions

in humans and mice, and in such context, it is possible that

IL-17 can increase the egress of hematopoietic stem/pro-

genitor cells from the bone marrow or may lead to the

relocation of bone marrow stem cell pools to peripheral

tissues. However, further studies to understand the exact

role and mechanisms of action by IL-17 as mobilizing

agent are needed.

Summary

In summary, data presented here demonstrated differen-

tially mediated IL-17 effects in different compartments of

hematopoiesis and confirmed that IL-17, as an important

component of adaptive immunity, is also part of a regula-

tory cytokine network involved in hematopoietic regula-

tory mechanisms, both during steady-state and altered

hematopoiesis (Fig. 1). However, given the complexity of

in vivo cytokine networks, mediator counter-regulations

and still not fully understood stem cell biology, accurate

conclusions on IL-17 hematopoietic effects are not

possible. However, dissecting the pathways by which IL-17

38 Immunology in Serbia (2012) 52:34–41

123

act on hematopoiesis is an important area for future

immunological and hematopoietic research.

Acknowledgments This research is supported by a grant (#175062)

from the Ministry of Education and Science, Republic of Serbia.

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Fig. 1 Effects of IL-17 on

different compartments of

hematopoiesis in bone marrow.

IL-17 is part of a regulatory

cytokine network involved in

hematopoietic regulatory

mechanisms. IL-17 stimulates

expansion, differentiation, and

mobilization of hematopoietic

and mesenchymal stem cells

principally through modulating

expression of different soluble

and membrane-bound factors by

bone marrow stroma. Blackarrows represent differentiation

pathways; HSC hematopoietic

stem cell; HPC hematopoietic

progenitor cells; MSCmesenchymal stem cell; MUmacrophage

Immunology in Serbia (2012) 52:34–41 39

123

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