Immunomodulatory Properties and Therapeutic Application of Bone
Marrow Derived-Mesenchymal Stem Cells
Ming Li Susumu Ikehara*
Department of Stem Cell Disorders, Kansai Medical University, Hirakata City, Osaka, Japan
- Corresponding Author:
- Susumu Ikehara
Department of Stem Cell Disorders
Kansai Medical University, Hirakata City
Osaka 570-1010, Japan
Tel: 81-72-804- 2450
E-mail: [email protected]
Received date: September 07, 2013; Accepted date: September 10, 2013; Published date: September 17, 2013
Citation: Li M, Ikehara S (2013) Immunomodulatory Properties and Therapeutic Application of Bone Marrow Derived-Mesenchymal Stem Cells. J Bone Marrow Res 1:131. doi:10.4172/2329-8820.1000131
Copyright: © 2013 Li M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Journal of Bone Research
Mesenchymal stem cells (MSCs) are prototypical adult stem cells, identified as an adherent, fibroblast-like population positive for CD105, CD90 and CD73, and lacking hematopietic markers. MSCs can be isolated from different adult tissues including bone marrow (BM), umbilical cord, skeletal muscle and adipose tissue. MSCs have a potent immunomodulatory function via soluble factors, including PGE2, TGF-β, indoleamine 2,3-dioxygenase (IDO), IL-10, and HGF. Treatment with MSCs can improve type 1 diabetes, liver fibrosis and arthritis via their immunomodulatory function. Intra-bone marrow bone marrow transplantation (IBM-BMT) can replace not only hemopoietic stem cells (HSCs) but also MSCs. IBM-BMT seems to be the best strategy for allogeneic BMT, and may improve aging-related diseases, including type 2 diabetes and osteoporosis. IBM-BMT has also been shown to be the most effective strategy to prevent the rejection of organ allografts. This review summarizes the immunomodulatory properties and therapeutic application of bone marrow derived-MSCs.
Mesenchymal stem cells; Hemopoietic stem cells; Hematopietic markers; Allogeneic BMT; Organ allografts
Mesenchymal stem cells (MSCs) are multi-potent progenitor cells isolated from bone marrow (BM)  and other adult tissue including skeletal muscle , adipose tissue , umbilical cord , synovium , the circulatory system , dental pulp , amniotic fluid , fetal blood  and lung . Friedenstein and coworkers  first reported the existence of adherent, fibroblast-like cells isolated from BM , and that these cells could differentiate into mesodermal lineage cells such as osteoblasts, adipocytes and chondrocytes in vitro  and cadiomyocytes . Also, MSCs have been reported to differentiate into types of cells of endodermal and ectodermal lineages, including lung , retinal pigment , skin , sebaceous duct cells , renal tubular cells , and neural cells [19,20], hepatocytes  and pancreatic islets . MSCs are characterized by plastic adherence, colony forming capacity, and the expression of the surface molecules CD73, CD90, and CD105 and the absence of the expression of hematopoietic lineage markers .
Recently, there have been reports indicating that MSCs secrete a variety of factors that promote tissue repair, stimulate proliferation and differentiation of endogenous tissue progenitors, and decrease inflammatory and immune reactions [24-26]. MSCs have been shown to modulate immunological responses via T-cell suppression [24,26-28]. The therapeutic benefit of MSCs extends to T cellmediated diseases such as graft-versus-host disease (GVHD) , Crohn’s disease  and the prevention of organ transplantation rejection . Moreover, MSCs have been observed to migrate to the site of injury in acute tissue injuries of kidney , liver , lung  and heart .
Adipose tissue and BM are the most readily available sources of MSCs because they are easy to harvest, and because of their relative abundance of progenitors and the lack of ethical concerns. Although adipose tissue-derived MSCs and bone marrow-derived MSCs (BMMSCs) show the same immunoregulatory functions and support of hematopoiesis , BMMSCs have a higher degree of commitment to differentiate into chondrogenic and osteogenic lineages than adipose tissue-derived MSCs . Herein, we focus on immumodulation of BMMSCs and their benefits in a variety of therapies.
BMMSCs Soluble Factors
BMMSCs have the ability to modify and influence almost all the cells of the innate and adaptive immune systems, to interfere with and affect cellular proliferation, differentiation, maturation, and function to induce an anti-inflammatory phenotype and to modulate the immune response mediated by BMMSC soluble factors, including IL-6, M-CSF, IL-10, TGF-β, HGF and PGE2 [26,38,39].
PGE2 synthesized from arachidonic acid is a lipid intermediate that has been identified as one of the candidates responsible for T cell inhibition by MSCs . PGE2 may have an immunostimulatory role by facilitating Th1 differentiation and expanding the Th17 T cell population . Prostaglandins act as paracrine and autocrine factors in the local environment where they are produced. BMMSCs also express receptors for prostaglandins. Expression of PGE2 was upregulated by IFN-γ and TNF-α in the BMMSCs for immunomodulatory function . Indoleamine 2,3 deoxygenase (IDO) is the rate-limiting enzyme involved in the catabolism of the essential amino acid tryptophan into its breakdown product kynurenine  and inhibition of T cell proliferation by dendritic cells (DCs) . BMMSCs can be induced to express IDO when stimulated by IFN-γ .
TGF-β1 and HGF represent MSC-derived molecules that have immunomodulatory activity on T cell responses . Mouse BMMSCs deliver their inhibitory activity via inducible nitric oxide synthase while rat BMMSCs preferentially use heme-oxygenase-1 . The production of nitric oxide by BMMSCs has also been suggested to suppress T cell proliferation via the phosphorylation of signal transducer and activator of transcription-5 (STAT5) [46,47].
Immunomodulation of BMMSCs
The innate immune cells include neutrophils, dendritic cells (DC), natural killer (NK) cells, eosinophils, mast cells and macrophages. MSCs have been shown to suppress these inflammatory cells , and to alter NK cell phenotype and suppress proliferation, cytokine secretion and cytotoxicity against HLA class I-expressing targets . The adaptive immune system which is composed of T and B lymphocytes, generates specific immune responses to pathogens with the production of memory cells. MSCs modulate DC function, indirectly regulate T and B cell activity, delay and prevent the development of acute graft versus host disease (GVHD)  and suppress DC function during allogeneic islet transplantation .
BMMSCs modulate different aspects of the rejection process, including the inhibition of DC differentiation , skewing of CD4+ T helper population phenotypes and modulation of CD8+ cytotoxic T lymphocyte and NK cell functions . BMMSCs strongly inhibited the maturation and functioning of monocyte-derived DCs by interfering selectively with the generation of immature cells via inhibitory mediator of MSC-derived PGE2 . However, one report has suggested that human adipose-derived MSCs are more potent in immunomodulating the differentiation of human DCs than BMMSCs . BMMSCs can inhibit the cytotoxic effects of antigen-primed cytotoxic T cells by suppressing the proliferation than activity  via the inhibition of the nuclear translocation of nuclear factor-kappa B . BMMSCs have been found to increase T reg cells when co-cultured with CD4+ cells in vitro , and to modulate immune response via inducing the generation of Treg in vitro . BMMSCs have been shown to suppress NK cell proliferation and IFN-γ production via the secretion of TGF- β1and PGE2 [26,59].
BMMSCs have been showen to inhibit the proliferation of B cells when stimulated with anti-CD40L and IL-4 . One report has suggested that allogeneic BMMSCs inhibit the activation, proliferation and IgG secretion of B cells in a BXSB mouse model of human systemic lupus erythematosus . BMMSCs have been shown to attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase cytokine release  (Figure 1).
Figure 1: Immunomodulatory functions of MSCs.
Immunomodulatory Functions of BMMSCs in the Animal Models
Allogeneic BMMSCs are effective in the treatment of murine models of human disease [63-65]. BMMSCs could secrete regulatory cytokines that affect regulatory T cells, and modulate the immunological dysregulation observed in antibody producing B cells and cytotoxic NK cells in the NOD mouse, a type 1 diabetes model mouse . BMMSCs promote the endogenous repair of pancreatic islets and renal glomeruli in a streptozotocin-induced diabetic mouse model . Co-infusion of BMMSCs and BM cells inhibited the beta cellsspecific T cell proliferation and restored insulin and glucose levels . Administration of BMMSCs increased the recovery of renal function by inhibiting the production of proinflammatory cytokines, such as IL- 1β,TNF, IFN-γ and through an anti-apoptotic effect on target cells .
BMMSCs secrete many cytokines and growth factors such as HGF , which shows anti-apoptotic activity in hepatocytes and plays an essential part in the regeneration of liver . CCl4-induced liver fibrosis is a classical experimental fibrosis model, and treatment with BMMSCs can protect against experimental liver fibrosis in CCl4- induced rats . BMMSCs potently inhibit in vitro T-cell proliferation in an IFN-γ-dependent mechanism that involves nitric oxide and PGE2. Moreover, anti-CD3-induced T-cell proliferation was suppressed by MSC treatment in the collagen-induced arthritis .
Intra Bone Marrow-BMT (IBM-BMT) for Metabolic Disorders and Organ Transplantation
BM transplantation (BMT) can be used to treat hematopoietic disorders, metabolic disorders and autoimmune diseases [23-26]. Allogeneic BMT can be used to treat autoimmune diseases [67-69]. Compared with intravenous BMT (IV-BMT), IBM-BMT  has been proven to be the most effective approach, since IBM-BMT can replace not only hemopoietic cells (including hemopoietic stem cells: HSCs) and BMMSCs to be recruited, thereby preventing the risk of graft rejection and allowing the use of a mild conditioning regimen. IBMBMT thus seems to be the best strategy for allogeneic BMT, since 1) no GVHD develops even if whole BM cells are injected; 2) no graft failure occurs even if the radiation dose is reduced; 3) hemopoietic recovery is rapid and 4) the restoration of T cell functions is complete even in donor-recipient combinations across MHC barriers .
As donor MSCs can be effectively recruited by “IBM-BMT”, we attempted to use the method to treat some disease in a mouse model. The SAMP6 mouse (a substrain of senescence-accelerated mice) spontaneously develops osteoporosis early in life and is therefore a useful model for examining the mechanisms underlying osteoporosis. After IBM-BMT, the hematolymphoid system was completely reconstituted with donor-type cells. Thus-treated SAMP6 mice (8 months after IBMBMT) showed marked increases in trabecular bone even at 20 months of age, and the bone mineral density (BMD) remained similar to that of normal B6 mice. BMMSCs in “IBM-BMT”-treated SAMP6 mice were replaced with donor MSCs [72,73].
We previously reported that the transplantation of BMMSCs via IBM-BMT in conjunction with the induction of HO-1 could eradicate type 2 diabetes. The beneficial effect of HO-1 induction further suggests that the abnormality in endothelial progenitor cells is due to mesenchymal stem cell-stromal cell disorder exacerbated by oxidative stress and decreases in adiponectin. Thus, the transplantation of BMMSCs using the IBM-BMT strategy in conjunction with HO-1 induction offers a novel approach in the treatment of type 2 diabetes . Another report has suggested that IBM-BMT is a viable method of immunological manipulation that suppresses the severe joint destruction and bone absorption in SKG/Jcl mice and lends further credence to the use of this methodology in humans with intractable rheumatoid arthritis .
We previously found that the combination of organ allografts and IBM-BMT from the same donors was the most effective strategy to prevent the rejection of organ allografts, since the radiation dose could be reduced to 4Gy x 2 in skin allografts [76,77]. In addition, we have found that IBM-BMT is applicable to allografts of other organs and tissues in rats and mice, such as pancreas islets, legs, lungs, heart and ovary [78-83] .
The original use of BMMSCs was to accelerate hematopoiesis, but BMMSCs have been shown to establish connection and modulate the activity of many cells of the immune system. The immunosuppressive effect of BMMSCs is beneficial for organ transplantation. MSCs as immunosuppressants have been used in clinical trials, but the longterm safety of the infusion of MSCs needs to be proven prior to their clinical application.
Conflict of Interests
None of the authors have conflicts of interest to declare.
We would like to thank Mr. Hilary Eastwick-Field and Ms. Keiko Ando for their help in the preparation of the manuscript.
- Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, et al. (2001) Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98: 2396-2402.
- Williams JT, Southerland SS, Souza J, Calcutt AF, Cartledge RG (1999) Cells isolated from adult human skeletal muscle capable of differentiating into multiple mesodermal phenotypes. Am Surg 65: 22-26.
- Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, et al. (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7: 211-228.
- Erices A, Conget P, Minguell JJ (2000) Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 109: 235-242.
- De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP (2001) Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 44: 1928-1942.
- Kuznetsov SA, Mankani MH, Gronthos S, Satomura K, Bianco P, et al. (2001) Circulating skeletal stem cells. J Cell Biol 153: 1133-1140.
- Gronthos S, Mankani M, Brahim J, Robey PG, Shi S (2000) Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A 97: 13625-13630.
- In 't Anker PS, Scherjon SA, Kleijburg-van der Keur C, Noort WA, Claas FH, et al. (2003) Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 102: 1548-1549.
- Noort WA, Kruisselbrink AB, in't Anker PS, Kruger M, van Bezooijen RL, et al. (2002) Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol 30: 870-878.
- Fan CG, Tang FW, Zhang QJ, Lu SH, Liu HY, et al. (2005) Characterization and neural differentiation of fetal lung mesenchymal stem cells. Cell Transplant 14: 311-321.
- Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3: 393-403.
- Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, et al. (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8: 315-317.
- Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, et al. (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103: 697-705.
- Ortiz LA, Gambelli F, McBride C, Gaupp D, Baddoo M, et al. (2003) Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects. Proc Natl Acad Sci U S A 100: 8407-8411.
- Arnhold S, Absenger Y, Klein H, Addicks K, Schraermeyer U (2007) Transplantation of bone marrow-derived mesenchymal stem cells rescue photoreceptor cells in the dystrophic retina of the rhodopsin knockout mouse. Graefes Arch Clin Exp Ophthalmol 245: 414-422.
- Nakagawa H, Akita S, Fukui M, Fujii T, Akino K (2005) Human mesenchymal stem cells successfully improve skin-substitute wound healing. Br J Dermatol 153: 29-36.
- Fu X, Fang L, Li X, Cheng B, Sheng Z (2006) Enhanced wound-healing quality with bone marrow mesenchymal stem cells autografting after skin injury. Wound Repair Regen 14: 325-335.
- Morigi M, Imberti B, Zoja C, Corna D, Tomasoni S, et al. (2004) Mesenchymal stem cells are renotropic, helping to repair the kidney and improve function in acute renal failure. J Am Soc Nephrol 15: 1794-1804.
- Kopen GC, Prockop DJ, Phinney DG (1999) Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A 96: 10711-10716.
- Muñoz-Elias G, Marcus AJ, Coyne TM, Woodbury D, Black IB (2004) Adult bone marrow stromal cells in the embryonic brain: engraftment, migration, differentiation, and long-term survival. J Neurosci 24: 4585-4595.
- Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, et al. (2002) Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 109: 1291-1302.
- Tang DQ, Cao LZ, Burkhardt BR, Xia CQ, Litherland SA, et al. (2004) In vivo and in vitro characterization of insulin-producing cells obtained from murine bone marrow. Diabetes 53: 1721-1732.
- Peister A, Mellad JA, Larson BL, Hall BM, Gibson LF, et al. (2004) Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood 103: 1662-1668.
- Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, et al. (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99: 3838-3843.
- Raffaghello L, Bianchi G, Bertolotto M, Montecucco F, Busca A, et al. (2008) Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells 26: 151-162.
- Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105: 1815-1822.
- Trim N, Morgan S, Evans M, Issa R, Fine D, et al. (2000) Hepatic stellate cells express the low affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation. Am J Pathol 156: 1235-1243.
- Meisel R, Zibert A, Laryea M, Göbel U, Däubener W, et al. (2004) Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 103: 4619-4621.
- Li H, Guo Z, Jiang X, Zhu H, Li X, et al. (2008) Mesenchymal stem cells alter migratory property of T and dendritic cells to delay the development of murine lethal acute graft-versus-host disease. Stem Cells 26: 2531-2541.
- García-Olmo D, García-Arranz M, Herreros D, Pascual I, Peiro C, et al. (2005) A phase I clinical trial of the treatment of Crohn's fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 48: 1416-1423.
- Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, et al. (2008) Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol 181: 3933-3946.
- Kunter U, Rong S, Djuric Z, Boor P, Müller-Newen G, et al. (2006) Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis. J Am Soc Nephrol 17: 2202-2212.
- van Poll D, Parekkadan B, Cho CH, Berthiaume F, Nahmias Y, et al. (2008) Mesenchymal stem cell-derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology 47: 1634-1643.
- Rojas M, Xu J, Woods CR, Mora AL, Spears W, et al. (2005) Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol 33: 145-152.
- Yokokawa M, Ohnishi S, Ishibashi-Ueda H, Obata H, Otani K, et al. (2008) Transplantation of mesenchymal stem cells improves atrioventricular conduction in a rat model of complete atrioventricular block. Cell Transplant 17: 1145-1155.
- Poloni A, Maurizi G, Leoni P, Serrani F, Mancini S, et al. (2012) Human dedifferentiated adipocytes show similar properties to bone marrow-derived mesenchymal stem cells. Stem Cells 30: 965-974.
- Gimble JM, Katz AJ, Bunnell BA (2007) Adipose-derived stem cells for regenerative medicine. Circ Res 100: 1249-1260.
- Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, et al. (2005) Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 105: 2214-2219.
- Ramasamy R, Fazekasova H, Lam EW, Soeiro I, Lombardi G, et al. (2007) Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 83: 71-76.
- English K, Ryan JM, Tobin L, Murphy MJ, Barry FP, et al. (2009) Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells. Clin Exp Immunol 156: 149-160.
- Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, et al. (2009) Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat Med 15: 633-640.
- English K, Barry FP, Field-Corbett CP, Mahon BP (2007) IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett 110: 91-100.
- Terness P, Bauer TM, Röse L, Dufter C, Watzlik A, et al. (2002) Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med 196: 447-457.
- Hwu P, Du MX, Lapointe R, Do M, Taylor MW, et al. (2000) Indoleamine 2,3-dioxygenase production by human dendritic cells results in the inhibition of T cell proliferation. J Immunol 164: 3596-3599.
- Dazzi F, Lopes L, Weng L (2012) Mesenchymal stromal cells: a key player in 'innate tolerance'? Immunology 137: 206-213.
- Sato K, Ozaki K, Oh I, Meguro A, Hatanaka K, et al. (2007) Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109: 228-234.
- Bingisser RM, Tilbrook PA, Holt PG, Kees UR (1998) Macrophage-derived nitric oxide regulates T cell activation via reversible disruption of the Jak3/STAT5 signaling pathway. J Immunol 160: 5729-5734.
- Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8: 726-736.
- Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 24: 74-85.
- Zhang B, Liu R, Shi D, Liu X, Chen Y, et al. (2009) Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population. Blood 113: 46-57.
- Aldinucci A, Rizzetto L, Pieri L, Nosi D, Romagnoli P, et al. (2010) Inhibition of immune synapse by altered dendritic cell actin distribution: a new pathway of mesenchymal stem cell immune regulation. J Immunol 185: 5102-5110.
- Urbán VS, Kiss J, Kovács J, Gócza E, Vas V, et al. (2008) Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 26: 244-253.
- Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23: 447-485.
- Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, et al. (2006) Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 103: 17438-17443.
- Tögel F, Hu Z, Weiss K, Isaac J, Lange C, et al. (2005) Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289: F31-42.
- Zhao DC, Lei JX, Chen R, Yu WH, Zhang XM, et al. (2005) Bone marrow-derived mesenchymal stem cells protect against experimental liver fibrosis in rats. World J Gastroenterol 11: 3431-3440.
- Matsuda-Hashii Y, Takai K, Ohta H, Fujisaki H, Tokimasa S, et al. (2004) Hepatocyte growth factor plays roles in the induction and autocrine maintenance of bone marrow stromal cell IL-11, SDF-1 alpha, and stem cell factor. Exp Hematol 32: 955-961.
- Di Ianni M, Del Papa B, De Ioanni M, Moretti L, Bonifacio E, et al. (2008) Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol 36: 309-318.
- Ryan JM, Barry F, Murphy JM, Mahon BP (2007) Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 149: 353-363.
- Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105: 2821-2827.
- Deng W, Han Q, Liao L, You S, Deng H, et al. (2005) Effects of allogeneic bone marrow-derived mesenchymal stem cells on T and B lymphocytes from BXSB mice. DNA Cell Biol 24: 458-463.
- Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, et al. (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15: 42-49.
- Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, et al. (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106: 1755-1761.
- Ding Y, Xu D, Feng G, Bushell A, Muschel RJ, et al. (2009) Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58: 1797-1806.
- Fiorina P, Jurewicz M, Augello A, Vergani A, Dada S, et al. (2009) Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 183: 993-1004.
- Schurgers E, Kelchtermans H, Mitera T, Geboes L, Matthys P (2010) Discrepancy between the in vitro and in vivo effects of murine mesenchymal stem cells on T-cell proliferation and collagen-induced arthritis. Arthritis Res Ther 12: R31.
- Oyaizu N, Yasumizu R, Miyama-Inaba M, Nomura S, Yoshida H, et al. (1988) (NZW x BXSB)F1 mouse. A new animal model of idiopathic thrombocytopenic purpura. J Exp Med 167: 2017-2022.
- Than S, Ishida H, Inaba M, Fukuba Y, Seino Y, et al. (1992) Bone marrow transplantation as a strategy for treatment of non-insulin-dependent diabetes mellitus in KK-Ay mice. J Exp Med 176: 1233-1238.
- Nishimura M, Toki J, Sugiura K, Hashimoto F, Tomita T, et al. (1994) Focal segmental glomerular sclerosis, a type of intractable chronic glomerulonephritis, is a stem cell disorder. J Exp Med 179: 1053-1058.
- Kushida T, Inaba M, Hisha H, Ichioka N, Esumi T, et al. (2001) Intra-bone marrow injection of allogeneic bone marrow cells: a powerful new strategy for treatment of intractable autoimmune diseases in MRL/lpr mice. Blood 97: 3292-3299.
- Ikehara S (2003) A novel strategy for allogeneic stem cell transplantation: perfusion method plus intra-bone marrow injection of stem cells. Exp Hematol 31: 1142-1146.
- Ichioka N, Inaba M, Kushida T, Esumi T, Takahara K, et al. (2002) Prevention of senile osteoporosis in SAMP6 mice by intrabone marrow injection of allogeneic bone marrow cells. Stem Cells 20: 542-551.
- Takada K, Inaba M, Ichioka N, Ueda Y, Taira M, et al. (2006) Treatment of senile osteoporosis in SAMP6 mice by intra-bone marrow injection of allogeneic bone marrow cells. Stem Cells 24: 399-405.
- Abraham NG, Li M, Vanella L, Peterson SJ, Ikehara S, et al. (2008) Bone marrow stem cell transplant into intra-bone cavity prevents type 2 diabetes: role of heme oxygenase-adiponectin. J Autoimmun 30: 128-135.
- Kushida T, Ueda Y, Umeda M, Oe K, Okamoto N, et al. (2009) Allogeneic intra-bone marrow transplantation prevents rheumatoid arthritis in SKG/Jcl mice. J Autoimmun 32: 216-222.
- Nakamura T, Good RA, Yasumizu R, Inoue S, Oo MM, et al. (1986) Successful liver allografts in mice by combination with allogeneic bone marrow transplantation. Proc Natl Acad Sci U S A 83: 4529-4532.
- Ikehara S (2008) A novel method of bone marrow transplantation (BMT) for intractable autoimmune diseases. J Autoimmun 30: 108-115.
- Kaneda H, Adachi Y, Saito Y, Ikebukuro K, Machida H, et al. (2005) Long-term observation after simultaneous lung and intra-bone marrow-bone marrow transplantation. J Heart Lung Transplant 24: 1415-1423.
- Guo K, Inaba M, Li M, An J, Cui W, et al. (2008) Long-term donor-specific tolerance in rat cardiac allografts by intrabone marrow injection of donor bone marrow cells. Transplantation 85: 93-101.
- Ikebukuro K, Adachi Y, Suzuki Y, Iwasaki M, Nakano K, et al. (2006) Synergistic effects of injection of bone marrow cells into both portal vein and bone marrow on tolerance induction in transplantation of allogeneic pancreatic islets. Bone Marrow Transplant 38: 657-664.
- Esumi T, Inaba M, Ichioka N, Kushida T, Iida H, et al. (2003) Successful allogeneic leg transplantation in rats in conjunction with intra-bone marrow injection of donor bone marrow cells. Transplantation 76: 1543-1548.
- Feng W, Cui Y, Zhan H, Shi M, Cui W, et al. (2010) Prevention of premature ovarian failure and osteoporosis induced by irradiation using allogeneic ovarian/bone marrow transplantation. Transplantation 89: 395-401.
- Feng W, Cui Y, Song C, Zhan H, Wang X, et al. (2007) Prevention of osteoporosis and hypogonadism by allogeneic ovarian transplantation in conjunction with intra-bone marrow-bone marrow transplantation. Transplantation 84: 1459-1466.