Regenerative and immunomodulatory potential of mesenchymal stem cells

Regenerative and immunomodulatory potential ofmesenchymal stem cellsMauro Krampera1, Annalisa Pasini1, Giovanni Pizzolo1,Lorenzo Cosmi2, Sergio Romagnani2 and Francesco Annunziato2

In the past few years, mesenchymal stem cells (MSCs)

have come into the limelight because of their multi-lineage

stem cell potential, which retains some aspects of embryonic

stem cells, and because of their characteristic

immunoregulatory functions exerted on different immune

effector cells. The regenerative and immunomodulatory

potential of MSCs has been used to support hemopoietic stem

cell engraftment; to repair or regenerate damaged or mutated

tissues, such as bone, cartilage, myocardial or hepatic tissues;

to interfere with neoplastic cell growth by transfecting MSCs

with anti-neoplastic molecules; and to modulate autoimmune

reactions such as collagenopathies, multiple sclerosis and

graft versus host disease. Thus, MSCs appear to be a very

promising tool for regenerative and immunoregulatory cell

therapy.

Addresses1 Department of Clinical and Experimental Medicine, Section of

Haematology, P.le L.A. Scuro 10, 37134 Verona, Italy2 Excellence Center of the University of Florence, University of

Florence, Viale Morgagni, 85, 50134 Firenze, Italy

Corresponding author: Krampera, Mauro ([email protected])

Current Opinion in Pharmacology 2006, 6:435–441

This review comes from a themed issue on

Immunomodulation

Edited by Marco Cassatella and Mauro Perretti

Available online 13th June 2006

1471-4892/$ – see front matter

# 2006 Elsevier Ltd. All rights reserved.

DOI 10.1016/j.coph.2006.02.008

IntroductionMesenchymal stem cells (MSCs) are adherent, fibroblast-

like, pluripotent, non-hematopoietic progenitor cells,

initially isolated from bone marrow, which have multi-

lineage differentiation potential (i.e the ability to differ-

entiate into various tissues of mesenchymal and non-

mesenchymal origin) [1,2]. MSCs can be found in many

different species, including humans, rodents and primates

[1–3,4�,5�,6,7], and in tissues other than bone marrow,

including both adult tissues such as fat [8�], hair follicles

and scalp subcutaneous tissue [9], and periodontal liga-

ment [10], and pre-natal tissues such as placenta [11],

umbilical cord blood [12], fetal bone marrow, blood, lung,

liver and spleen [13].

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In the past few years, it has become clear that MSCs also

possess immunoregulatory properties, inasmuch as they

can:

1. I
nhibit the function of mature T cells following their
activation by non-specific mitogens [14].

2. D
ramatically downregulate the response of naı̈ve and
memory antigen-specific T cells to their cognate

peptide in mice [15].

3. S
ignificantly prolong the survival of major histocom-
patibility complex (MHC)-mismatched skin grafts

after infusion in baboons and reduce the incidence of

graft-versus-host disease (GvHD) after allogeneic

hematopoietic stem cell (HSC) transplantation in

humans [16,17].

4. C
ure severe acute GvHD refractory to conventional
immunosuppressive therapy [18��].
5. A meliorate experimental autoimmune encephalomye-
litis in mice [19�].

Recently, mesenchymal cell precursors with similar im-

munophenotype and immunomodulatory functions to

bone marrow MSCs, and multilineage differentiation p-

otential for different tissues, including osteocytes, chon-

drocytes, adipocytes and neural cells, have been obtained

from adult mouse and human lymphoid tissues such as

spleen and thymus (Krampera M et al., unpublished).

This evidence suggests that a MSC system may persist in

adults as a reservoir for tissue turnover. Some factors such

as basis fibroblast growth factor or heparin-binding growth

factor-like growth factor, in addition to increasing MSC

proliferation rate, might also interfere with their differ-

entiation processes and maintain MSCs in a multipotent

status [4�]. Similar to hemopoietic stem cells, it has been

shown that circulating MSCs are detectable in peripheral

blood [20�], suggesting that mesenchymal tissue compart-

ments could be supported by circulating MSCs, as specu-

lated by Cohnheim in 1867. In addition, a process of MSC

aging has been described, which implies a decrease in

both the number of MSCs and their differentiation poten-

tial, at least in bone marrow [21]. This evidence can e-

xplain the lower capacity of tissue to self-repair with

increasing age and, therefore, might justify the therapeu-

tical strategies of MSC transplantation in cases of tissue

degeneration.

MSC properties are here discussed, on the basis of the

main literature data, with major emphasis on their pos-

sible therapeutic implications. At present, MSCs can be


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http://dx.doi.org/10.1016/j.coph.2006.02.008

436 Immunomodulation

chacterised by their immunophenotypic and functional

properties, and their regenerative and immunomodula-

tory potential could be used for tissue repair and control of

abnormal or autoaggressive immune reactions.

Phenotype of in vitro cultured MSCsMSCs are normally obtained from cell suspensions

derived from bone marrow samples or disgregated tissues.

Cells can be cultured in plates or flasks at different

concentrations in complete media (i.e. modified Eagle

medium containing serum and antibiotics) at 37 8C in a

5% CO2 atmosphere. After a few hours, some cells adhere

to the plastic surface (non-adherent cells are removed 2–3

days later) and form proliferating, fibroblastic-like cell

clusters that are called fibroblast colony forming units,

which can be quantified after 10 days [1,2,4�,5�]. Adher-

ent cells normally grow quickly and have to be split and

expanded in larger flasks before they become confluent;

otherwise, they stop growing and tend to differentiate

into pre-adipocytes. A homogenous cell population can be

obtained after 3–5 weeks of culture and can proliferate

without spontaneously differentiating for up to 40 gen-

erations [1,2,4�,5�].

There are no specific markers for MSCs: they are recog-

nized on the basis of a complex immunophenotype,

including the lack of hematopoietic stem cell markers

(such as CD45 and CD34), as well as lack of endothelial

markers (such as CD31 or PECAM-1), and the expression

of a number of surface molecules such as CD105, CD73,

CD106 (vascular cellular adhesion molecule-1), CD54

(intercellular adhesional molecule-1), CD44, CD90,

CD29 and STRO-1 [1–3,4�,5�]. Other markers, including

cytokine receptors, molecules involved in immune

responses (e.g. MHC class I and II, CD119/interferon

[IFN]-g receptor) and chemokines, can also be expressed

by MSCs [3,4�,5�] (Table 1).

Differentiation and regenerative potentialMSCs express low levels of markers that are shared by

neural (nestin), endothelial (CD106), and epithelial

(human epidermal groth factor receptor-1) cells [1–3,4�].In addition, microarray analysis shows that MSCs express

embryonic stem cell markers, such as Hox [22�], thus

suggesting that their differentiation potential may be

broad. MSCs can differentiate into various tissues of

mesenchymal origin, including bone marrow stromal cells,

adipocytes, osteoblasts, chondrocytes, tenocytes, skeletal

myocytes and cells of visceral mesoderm [1–3,4�,5�,6]. In

addition, MSCs can differentiate into tissues of ectodermal

(e.g. neurons) [23] and endodermal (e.g. hepatocytes)

origin [24]. On the basis of this evidence, it has been

proposed that it is possible to discriminate between

mesenchymal progenitor cells (marrow stromal precur-

sors), which retain only mesenchymal differentiation

potential, and true MSCs, which can also differentiate

into tissues of ectodermal or endodermal origin [2]. The


multilineage differentiation potential of adherent stromal

cells can be assessed in vitro with functional assays using

specific differentiation media [1–3,4�,5�,6] (Figure 1).

Systemic infusion of ex vivo expanded autologous MSCs is

feasible and safe in the short-term [7,25]. Exogenously

administered MSCs spread into all tissues, but preferen-

tially survive and proliferate in the presence of regener-

ating tissues and proliferating malignant cells, and are

thus incorporated into the tissue architecture as stromal

fibroblasts, preferentially interacting with and supporting

neoplastic cell growth. For this reason, engineered MSCs

might also be used as an intratumour source of therapeu-

tics [26�].

MSCs interact with hematopoietic stem cells, influencing

their homing and differentiation through cell–cell contact

and the production of factors and chemokines. As such,

MSCs can be co-transplanted with hemopoietic stem cells

to improve their engraftment in bone marrow [25]. MSCs

have been used to repair or regenerate damaged or

mutated bone, cartilage [27], myocardial [28] or hepatic

tissues [29]. An increasing amount of data highlights the

potential usefulness of MSCs in ameliorating the clinical

signs of diseases such as osteogenesis imperfecta [30],

dental structure degeneration [31�], heart infarction [32�]and ischemic brain stroke [33]. The effectiveness of MSC

infusion in neurodegenerative diseases is still debated,

although in some conditions the immunomodulatory

effect of MSCs could be more important than their

regenerative potential [19�].

Immunomodulatory potentialBesides their regenerative capacity, MSCs also possess

immunoregulatory properties: they can suppress immune

reactions both in vitro and in vivo in a non-MHC-

restricted manner [4�,34]. Functional interactions

between bone marrow stromal cells and T lymphocytes

have been described in particular conditions, such as the

absence of thymus or HSC transplantation. In thymecto-

mized mice, the majority of T cells adhering to bone

marrow stroma exhibit an immature phenotype, thus

indicating that the bone marrow microenvironment pro-

vides an appropriate support for T cell development [35].

Moreover, after HSC transplantation in humans, bone

marrow stromal cells migrate to the thymus, where they

participate in the positive selection of thymocytes [36].

Mouse bone marrow-derived MSCs dramatically down-

regulate the response of naı̈ve and memory antigen-

specific T cells to their cognate peptide; this effect is

primarily cell contact dependent [15]. In addition, MSCs

significantly prolong the survival of MHC-mismatched

skin grafts after infusion in baboons, reduce the incidence

of GvHD after allogeneic HSC transplantation in

humans, and effectively ameliorate experimental auto-

immune encephalomyelitis in mice [16,17,19�]. Finally,


Regenerative and immunomodulatory potential of mesenchymal stem cells Krampera et al. 437

Table 1

Human MSC immunophenotype as the result of the combination of positive and negative, lineage-specific and functional markers.

Marker Marker expression

MSC-associated marker combination CD105 (SH2/TGFb receptor) ++

CD73 (SH3 and SH4) ++

CD29 ++

CD44 +++

CD90 +++

Endothelial markers CD106 �CD31 �

Hemopoietic markers CD45 �CD34 �CD13 +

CD14 �CD10 �CD56 �

MHC molecules HLA class I (A,B,C) ++a

HLA-DR �a

Adhesion molecules (in addition to CD44 and CD29) CD11c �CD18 �CD54 (ICAM-1) +

CD49a +

CD49b +

CD49c +

CD49d �CD49e +

CD62L +

CD166 +

Costimulatory molecules CD80 �CD86 �

Cytokine receptors(in addition to CD105) CD117 �CD119 +

CD25 �CD122 �CD124 �

Tumor necrosis factor family molecules CD120a +

CD120b +

CD30 �CD30L (CD153) �CD40 �CD40L (CD154) �FasL �/�Fas (CD95) ++

TRAIL �TRAIL-R �

Epidermal growth factor-family molecules HB-EGF �EGFR-1 (HER-1) +

EGFR-4 (HER-4) �

Chemokine-family molecules CXCR4 –/� (subset)

CXCL12 �a Upregulated by IFN-g.�: negative;�: weak expression of markers; +, ++, +++: marker expression with 1, 2, and 3 log shift of intensity as compared

with negative control, respectively. EGFR, epithelial growth factor receptor; HER, human epidermal growth factor receptor-1; HLA, human leukocyte

antigen; ICAM, intercellular adhesion molecule; TRAIL, tumour necrosis factor-related apoptosis-inducing ligand.

third party haploidentical (mother-derived) MSCs can be

safely infused to treat severe acute GvHD that is refrac-

tory to conventional immunosuppressive therapy [18��].MSCs can inhibit nearly all cells participating in the

immune response, inasmuch as they suppress several

functions of naive and memory T cells [5�,15,16,37�,38,


39�], B cells [5�,39�,40�] and natural killer cells [5�,41,42�],as well as the differentiation and function of monocytes-

derived dendritic cells [43,44�].

At present, the exact mechanism responsible for MSC-

mediated immunosuppression is not fully clarified.



Figure 1

Assessment of MSC multilineage differentiation potential by functional assays based on specific differentiation media. Adipocyte differentiation

is achieved after three weeks of culture of MSCs with adipogenic medium containing 10�6 M dexamethasone, 10 mg/ml insulin and 100 mg/ml

3-isobutyl-1-methylxantine. Osteoblast differentiation is achieved after three weeks of culture with osteogenic medium containing 10�7 M

dexamethasone, 50 mg/mL ascorbic acid and 10 mM b-glycerophosphate. Chondrocyte differentiation is achieved after three weeks of culture

with chondrogenic medium containing 10�7 M dexamethasone, 10 ng/ml TGF-b1, 50 mg/mL ascorbic acid and 40 mg/mL proline. Neural

differentiation is achieved with neural medium (modified by Woodbury [23]) containing Dulbecco’s modified eagle medium and fetal bovine

serum supplemented with 5 ng/ml basic fibroblast growth factor for 24 hours; after this pre-induction, cells are washed with phosphate-buffered

saline and induction medium (containing DMEM with N2 supplement, butylated hydroxyanisole, KCl, valproic acid and forskolin) is added for

2–16 hours. Oil-red-O, von Kossa and toluidine blu dyes are employed to identify adipocytes, osteoblasts and chondrocytes, respectively.

Neural morphology is characterized by scanning electron microscopy. Pluripotency of MSCs is shown by their ability to differentiate into

tissues of both mesodermal (adipocytes, osteocytes and chondrocytes) and ectodermal (neural cells) origin.

Soluble factors as well as contact-dependent mechanisms

have been shown to be implicated in the suppressive

activity of MSCs [5�,14–16,37�,38,39�,40�,41,42�43,44�,45�]. However, by using a double-chamber culture system

in which MSCs and target cells were separated by a semi-

permeable membrane that allows the diffusion of mole-

cules in the absence of cell contact, it has been clearly

demonstrated [5�], in accordance with previous reports

[18��,39�,46,47], that, at least for human-derived MSCs,

Figure 2

IFN-g-dependent MSC inhibitory effect: a model. Activated CD4+ and CD8+

mechanism(s) through binding to the IFN-g-receptor (IFN-g-R) expressed by

sensitive to MSC inhibitory mechanism(s) under the effect of IFN-g produce

inhibitory mechanism(s) by their own IFN-g production, whereas activated d

still undefined, mechanisms.


the suppressive activity does not depend upon cell–cell

contact.

Among many soluble factors, transforming growth factor

(TGF)-b1, hepathocytes growth factor [14,41], prosta-

glandin E2 (PGE2) [41,45�] and indoleamine 2,3-dioxy-

genase (IDO) [5�,37�,48] have been indicated as possible

candidates involved in the immunosuppressive acti-

vity of human MSCs. However, recent reports clearly

T cells release IFN-g that, in turn, triggers MSCs’ inhibitory

MSCs. Activated B cells, normally unaffected by MSCs, become

d by T cells. Activated natural killer (NK) cells trigger MSCs’

endritic cells are inhibited by MSCs via PGE2 and probably other,



demonstrated that neutralization of TGF-b1 did not

reverse the suppressive activity of MSCs [5�,45�,49].

It is well-established that IFN-g plays an important role

in the enhancement of MSCs’ suppressive activity [50].

In agreement with this observation, we have recently

shown that, in culture, the addition of a neutralizing

anti-IFN-g receptor monoclonal antibody consistently

inhibited the suppressive activity of MSCs on both

CD4+ and CD8+ T cells, and even on natural killer cells

[5�]. The crucial role of IFN-g in MSC-driven suppres-

sion was further supported by the fact that MSCs had no

inhibitory effect on the proliferation of purified

CD4+CRTH2+ T cells, which represent a pure popula-

tion of Th2 cells able to produce interleukin-4, but not

IFN-g [5�].

The mechanisms by which IFN-g can trigger, or con-

tribute to, the immunosuppressive activity of MSCs has

been linked to the ability of human MSCs to express

IDO, which catalyzes the conversion of tryptophan to

kynurenine, and the expression of which is upregulated

by IFN-g itself [5�,37�]. Accordingly, neutralization of

IDO activity, by using competitive inhibitors or the

addition in culture of exogenous tryptophan, partially

but substantially inhibited the suppressive activity

exerted by MSCs on T cell proliferation [5�,37�]. Con-

sistent with this observation, it has recently been demon-

strated that PGE2 is involved in the suppressive activity

exerted by human MSCs [41,45�], which has been shown,

similarly to IDO, to be induced by IFN-g (Figure 2) [45�].

More recently, it has been reported that MSCs can exert

their suppressive activity by inducing an increase in the

numbers of CD4+CD25+ regulatory T cells in the target

population [45�]. However, in our study, we found that

CD25 and cytotoxic T lymphocyte-associated antigen-4

(CTLA-4) surface expression, and Foxp3 mRNA levels,

were not dependent upon whether CD4+ T cells were

cultured in the presence of MSCs [5�]. More importantly,

no significant differences were observed in the suppres-

sive activity of MSCs on the proliferation induced by

allogeneic stimulation of either total CD4+ T cells or

CD25-depleted CD4+ T cells [5�].

Potential therapeutic usesBecause of their biological characteristics, MSCs may be

suitable for:

1. D

ww

egenerative and inflammatory diseases involving

bone, cartilage, tendon and muscle tissues, through the

use of natural or synthetic biomaterials (e.g. hydro-

xyapatite or tricalcium phosphate) as carriers for MSC

delivery to the damaged tissue [30,31�,51].

2. H
ematopoietic stem cell transplantation, as support for
hematopoiesis and precvention treatment of GvHD

[17,18��,25].

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3. A
utoimmune diseases that are refractory to conven-
tional treatments [19�].
4. A nti-cancer treatments, to deliver molecules with
inhibitory effects on neoplastic cells [26�].

Conclusions
In the past few years, there has been a dramatic improve-
ment in our understanding of the biology and the poten-

tial clinical use of MSCs. Data in the literature concerning

cell expansion and functional characterization of MSCs,

as well as their regenerative and immunomodulatory

properties, are vast and sometimes contradictory. How-

ever, this gap of information has not hampered the

beginning of therapeutic trials that should soon clarify

whether these cells will be useful for the treatment of

some human diseases. In this respect, the feasibility of

gene transfer procedures into MSCs will probably

increase the range of their clinical utilization.

UpdateRecent work has shown that MSCs can repair scarred

myocardium after myocardial infarction, thus supporting

previous contradictory evidence of MSC regenerative

potential in heart diseases [52]. In addition, MSCs seem

to be useful in congenital myopathies such as Duchenne

muscular dystrophy [53].

AcknowledgmentsThis work was supported by Italian Ministry of University and ScientificResearch, Italian Association for Cancer Research (AIRC), ItalianNational Research Council (CNR), Fondazione Cariverona, and by theMinistry of Health of Tuscany Region.

References and recommended readingPapers of particular interest, published within the annual period ofreview, have been highlighted as:

� of special interest�� of outstanding interest

1. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R,Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR:Multilineage potential of adult human mesenchymal stemcells. Science 1999, 284:143-147.

2. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD,Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M et al.:Pluripotency of mesenchymal stem cells derived from adultmarrow. Nature 2002, 418:41-49.

3. Tremain N, Korkko J, Ibberson D, Kopen GC, DiGirolamo C,Phinnet DG: MicroSAGE analysis of 2,353 expressed genes in asingle cell-derived colony of undifferentiated humanmesenchymal stem cells reveals mRNAs of multiple celllineages. Stem Cells 2001, 19:408-418.

4.�

Krampera M, Pasini A, Rigo A, Scupoli MT, Tecchio C, Malpeli G,Scarpa A, Dazzi F, Pizzolo G, Vinante F: HB-EGF/HER-1signalling in bone marrow mesenchymal stem cells: inducingcell expansion and reversibly preventing multi-lineagedifferentiation. Blood 2005, 106:59-66.

An epithelial growth factor influences MSC differentiation.

5.�

Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A,Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F et al.: Role of theIFN-g in the immunomodulatory activity of humanmesenchymal stem cells. Stem cells 2005, 24:386-398.

IFN-g, besides activating immune responses, induces MSC regulatoryeffects.



6. Phinney DG, Kopen G, Isaacson RL, Prockop D: Plastic adherentstromal cells from the bone marrow of commonly used strainsof inbred mice: variation in yield, growth, and differentiation.J Cell Biochem 1999, 72:570-585.

7. Devine SM, Bartholomew AM, Mahmud N, Nelson M, Patil S,Hardy W, Sturgeon C, Hewett T, Chung T, Stock W et al.:Mesenchymal stem cells are capable of homing to the bonemarrow of non-human primates following systemic infusion.Exp Hematol 2001, 29:244-255.

8.�

Lee RH, Kim B, Choi I, Kim H, Choi HS, Suh K, Bae YC, Jung JS:Characterization and expression analysis of mesenchymalstem cells from human bone marrow and adipose tissue.Cell Physiol Biochem 2004, 14:311-324.

Fat is a comparable alternative source of MSCs to bone marrow.

9. Shih DT, Lee DC, Chen SC, Tsai RY, Huang CT, Tsai CC, Shen EY,Chiu WT: Isolation and characterization of neurogenicmesenchymal stem cells in human scalp tissue. Stem Cells2005, 23:1012-1020.

10. Trubiani O, Di Primio R, Traini T, Pizzicannella J, Scarano A,Piattelli A, Caputi S: Morphological and cytofluorimetricanalysis of adult mesenchymal stem cells expanded ex vivofrom periodontal ligament. Int J Immunopathol Pharmacol 2005,18:213-221.

11. In’t Anker PS, Scherjon SA, Kleijburg-van der Keur C,de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH:Isolation of mesenchymal stem cells of fetal and maternalorigin from human placenta. Stem Cells 2004, 22:1338-1345.

12. Erices A, Conget P, Minguel JJ: Mesenchymal progenitorcells in human umbelical cord blood. Br J Haematol 2000,109:235-242.

13. In’t Anker PS, Noort WA, Scherjon SA, Kleijburg-van der Keur C,Kruisselbrink AB, van Bezooijen RL, Beekhuizen W, Willemze R,Kanhai HHH, Fibbe WE: Mesenchymal stem cells in humansecond-trimester bone marrow, liver, lung, and spleen exibit asimilar immunophenotype but a heterogeneuous multilineagedifferentiation potential. Haematologica 2003, 88:845-852.

14. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD,Matteucci P, Grisanti S, Gianni AM: Human bone marrowstromal cells suppress T-lymphocyte proliferation inducedby cellular or nonspecific mitogenic stimuli. Blood 2002,99:3838-3843.

15. Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E,Dazzi F: Bone marrow mesenchymal stem cells inhibit theresponse of naı̈ve and memory antigen-specific T cells to theircognate peptide. Blood 2003, 101:3722-3729.

16. Bartholomew A, Sturgeon C, Siatskas M, Ferrer K, McIntosh K,Patil S, Hardy W, Devine S, Ucker D, Deans R et al.: Mesenchymalstem cells suppress lymphocyte proliferation in vitroand prolong skin graft survival in vivo. Exp Hematol 2002,30:42-48.

17. Lazarus HM, Koc ON, Devine SM, Curtin P, Maziarz RT,Holland HK, Shpall EJ, McCarthy P, Atkinson K, Cooper BW et al.:Cotransplantation of HLA-identical sibling culture-expandedmesenchymal stem cells and hematopoietic stem cells inhematologic malignancy patients. Biol Blood Marrow Transplant2005, 11:389-398.

18.��

Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M,Uzunel M, Ringden O: Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymalstem cells. Lancet 2004, 363:1439-1441.

This is the first evidence of dramatic downmodulation of an allogeneicimmune rection in humans.

19.�

Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I,Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F et al.:Mesenchymal stem cells ameliorate experimentalautoimmune encephalomyelitis inducing T cell anergy.Blood 2005, 106:1755-1761.

MSCs are potent inhibitors of autoimmunity in vivo.

20.�

Roufosse CA, Direkze NC, Otto WR, Wright NA: Circulatingmesenchymal stem cells. Int J Biochem Cell Biol 2004,36:585-597.

An interesting review concerning the problem of MSC migration.


21. D’Ippolito G, Schiller PC, Ricordi C, Roos BA, Howard GA:Age-related osteogenic potential of mesenchymal stromalstem cells from human vertebral bone marrow. J Bone MinerRes 1999, 14:1115-1122.

22.�

Phinney DG, Gray AJ, Hill K, Pandey A: Murine mesenchymal andembryonic stem cells express a similar Hox gene profile.Biochem Biophys Res Commun 2005, 338:1759-1765.

MSCs retain embryonic stem cell properties, which explains their multi-lineage differentiation potential.

23. Woodbury D, Schwarz EJ, Prockop DJ, Black IB: Adult rat andhuman bone marrow stromal cells differentiate into neurons.J Neurosci Res 2000, 61:364-370.

24. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK,Murase N, Boggs SS, Greenberger JS, Goff JP: Bone marrowas a potential source of hepatic oval cells. Science 1999,284:1168-1170.

25. Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE,Caplan AI, Lazarus HM: Rapid hematopoietic recovery aftercoinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advancedbreast cancer patients receiving high-dose chemotherapy.J Clin Oncol 2000, 18:307-316.

26.�

Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J,Chen J, Hentschel S, Vecil G, Dembinski J et al.: Human bonemarrow-derived mesenchymal stem cells in the treatment ofgliomas. Cancer Res 2005, 65:3307-3318.

Clear evidence of the potential in vivo use of MSCs for anti-cancertherapy.

27. Pereira RF, Halford KW, O’Hara MD, Leeper DB, Sokolov BP,Pollard MD, Bagasra O, Prockop DJ: Cultured adherent cellsfrom marrow can serve as long-lasting precursor cells forbone, cartilage, and lung in irradiated mice. Proc Natl Acad SciUSA 1995, 92:4857-4861.

28. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD:Human mesenchymal stem cells differentiate to acardiomyocyte phenotype in the adult murine heart.Circulation 2002, 105:93-98.

29. Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M,Lund T, Lenvik T, Johnson S, Hu WS, Verfaillie CM: Multipotentadult progenitor cells from bone marrow differentiate intofunctional hepatocyte-like cells. J Clin Invest 2002,109:1291-1302.

30. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL,Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK:Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesisimperfecta. Nat Med 1999, 5:309-313.

31.�

Shi S, Bartold PM, Miura M, Seo BM, Robey PG, Gronthos S:The efficacy of mesenchymal stem cells to regenerate andrepair dental structures. Orthod Craniofac Res 2005, 8:191-199.

Different and broad usefulness of MSC transplantation.

32.�

Dai W, Hale SL, Martin BJ, Kuang JQ, Dow JS, Wold LE, Kloner RA:Allogeneic mesenchymal stem cell transplantation inpostinfarcted rat myocardium: short- and long-term effects.Circulation 2005, 112:214-223.

Further evidence of a potential use of MSCs in heart infarction.

33. Bang OY, Lee JS, Lee PH, Lee G: Autologous mesenchymalstem cell transplantation in stroke patients. Ann Neurol 2005,57:874-882.

34. Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O:Mesenchymal stem cells inhibit and stimulate mixedlymphocyte cultures and mitogenic responses independentlyof the major histocompatibility complex. Scand J Immunol2003, 57:11-20.

35. Barda-Saad M, Rozenszajn LA, Globerson A, Zhang AS, Zipori D:Selective adhesion of immature thymocytes to bone marrowstromal cells: relevance to T cell lymphopoiesis. Exp Hematol1996, 24:386-391.

36. Li Y, Hisha H, Inaba M, Lian Z, Yu C, Kawamura M, Yamamoto Y,Nishio N, Toki J, Fan H, Ikehara S: Evidence for migration ofdonor bone marrow stromal cells into recipient thymus after



bone marrow transplantation plus bone grafts: a role ofstromal cells in positive selection. Exp Hematol 2000,28:950-960.

37.�

Meisel R, Zibert A, Laryea M, Gobel U, Daubener W, Dilloo D:Human bone marrow stromal cells inhibit allogeneic T-cellresponses by indoleamine 2,3-dioxygenase mediatedtryptophan degradation. Blood 2004, 103:4619-4621.

One of the mechanisms involved in the inihibitory effect of MSCs has beenidentified.

38. Rasmusson I, Ringden O, Sundberg B, Le Blanc K: Mesenchymalstem cells inhibit the formation of cytotoxic T lymphocytes,but not activated cytotoxic T lymphocytes or natural killercells. Transplantation 2003, 76:1208-1213.

39.�

Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F: Bone marrowmesenchymal stem cells induce division arrest anergy ofactivated T cells. Blood 2005, 105:2821-2827.

A further clarification of the inihibitory effects of MSCs in mice.

40.�

Corcione A, Benvenuto F, Ferretti E, Giunti D, Cappiello V,Cazzanti F, Risso M, Gualandi F, Mancardi GL, Pistoia V, Uccelli A:Human mesenchymal stem cells modulate B-cell functions.Blood 2006, 107:367-372.

Clear evidence that even humoral immunity is affected by MSCs.

41. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN,Papamichail M: Interactions between human mesenchymalstem cells and natural killer cells. Stem Cells 2006, 24:74-85.

42.�

Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L:Mesenchymal stem cell (MSC)/natural killer (NK) cellinteractions: evidence that activated NK cells are capable ofkilling MSC while MSC can inhibit IL-2-induced NK cellproliferation. Blood 2006, 107:1484-1490.

Not only adaptive, but also innate, immune effector cells can be regulatedby MSCs.

43. Zhang W, Ge W, Li C, You S, Liao L, Han Q, Deng W, Zhao RC:Effects of mesenchymal stem cells on differentiation,maturation, and function of human monocyte-deriveddendritic cells. Stem Cells Dev 2004, 13:263-271.

44.�

Jiang XX, Zhang Y, Liu B, Zhang SX, Wu Y, Yu XD, Mao N: Humanmesenchymal stem cells inhibit differentiation and function ofmonocyte-derived dendritic cells. Blood 2005, 105:4120-4126.

The inihibitory effects of MSCs begin from antigen presentation.


45.�

Aggarwal S, Pittenger MF: Human mesenchymal stem cellsmodulate allogeneic immune cell responses. Blood 2004,105:1815-1822.

Different soluble factors are suggested as mediators of the inihibitoryeffects of MSCs in humans.

46. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC:Suppression of allogeneic T-cell proliferation by humanmarrow stromal cells: implications in trasplantation.Transplantation 2003, 75:389-397.

47. Rasmusson I, Ringden O, Sundberg B, Le Blanc K: Mesenchymalstem cell inhibit lymphocytes proliferation by mitogens andalloantigens by different mechanisms. Exp Cell Res 2005,305:33-41.

48. Plumas J, Chaperot L, Richard MJ, Molens JP, Bensa JC,Favrot MC: Mesenchymal stem cells induce apoptosis ofactivated T cells. Leukemia 2005, 19:1597-1604.

49. Le Blanc K, Rasmusson I, Gotherstrom C, Seidel C,Sundberg B, Sundin M, Rosendahl K, Tammik C,Ringden O: Mesenchymal stem cell inhibit the expressionof CD25 (interleukine-2 receptor) and CD38 onphytohaemagglutinin-activated lymphocytes. Scand JImmunol 2004, 60:307-315.

50. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O:HLA expression and immunologic properties of differentiatedand undifferentiated mesenchymal stem cells. Exp Hematol2003, 31:890-896.

51. Petite H, Viateau V, Bensaid W, Meunier A, de Pollak C,Bourguignon M, Oudina K, Sedel L, Guillemin G: Tissue-engineered bone regeneration. Nat Biotechnol 2000,18:959-963.

52. Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H,Ishino K, Ishida H, Shimizu T, Kangawa K et al.: Monolayeredmesenchymal stem cells repair scarred myocardium aftermyocardial infarction. Nat Med 2006, 12:459-465.

53. Goncalves MA, de Vries AA, Holkers M, van de Watering MJ,van der Velde I, van Nierop GP, Valerio D, Knaan-Shanzer S:Human mesenchymal stem cells ectopically expressingfull-length dystrophin can complement Duchenne musculardystrophy myotubes by cell fusion. Hum Mol Genet 2006,15:213-221.


Regenerative and immunomodulatory potential of mesenchymal stem cells

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