Mesenchymal stromal cells for organ transplantation: Different sources and unique characteristics?

PURPOSE OF THE REVIEW: In this review, recent findings on the effects of tissue and donor origin, culturing conditions and preconditioning regimens on the therapeutic effect of mesenchymal stem cells (MSC) in organ transplantation are discussed and the importance of understanding the characteristics of MSC for developing efficient therapy is stressed. RECENT FINDINGS: MSC research in organ transplantation is currently moving from safety-feasibility studies to efficacy studies and finding the optimal MSC for therapy is therefore highly relevant. Although sharing basic properties, there are subtle differences between MSC from different tissue sources that may affect their efficacy. Furthermore, the use of MSC from diseased organ recipients, donor or third party may affect their therapeutic effect. The importance of these differences in MSC properties may however be overshadowed by the impact of culture conditions on MSC. Culture conditions dramatically change the characteristics of MSC, and this situation can be exploited by exposing MSC to preconditioning treatment to bring about the desired properties in MSC. As MSC appear to be short-lived after infusion, the specific characteristics of MSC are mostly relevant for short-term interactions between MSC and host cells, which will subsequently take over the effects of MSC. The multiple effects of MSC are by no means unique, but the full spectrum of the effects in combination with their easy isolation and expansion make MSC a suitable cell type for therapy. SUMMARY: Tissue source, donor source and culture conditions affect the phenotypical and functional properties of MSC. The efficacy of MSC therapy will therefore depend on the source and manipulation of MSC

Toward development of imesenchymal stem cells for immunomodulatory therapy

Mesenchymal stem cells (MSC) are under development as an immunomodulatory therapy. The anticipated immunomodulatory effects of MSC are broad, from direct inhibition of lymphocyte proliferation, induction of regulatory T and B cells, to resetting the immune system via a hit-and-run principle. There are endless flavors of MSC. Differences between MSC are originating from donors variation, differences in tissue of origin, the effects of culture conditions, and expansion time. Even standard culture conditions change the properties of MSC dramatically and generate MSC that only remotely resemble their in vivo counterparts. Adjustments in culture protocols can further emphasize properties of interest in MSC, thereby generating cells fitted for specific purposes. Culture improved immunomodulatory MSC can be designed to target particular immune disorders. In this review, we describe the observed and the desired immunomodulatory effects of MSC and propose approaches how MSC with optimal immunomodulatory properties can be developed

Morphology and size of stem cells from mouse and whale: Observational study

Abstract Objective To compare the morphology and size of stem cells from two mammals of noticeably different body size. Design Observational study. Setting The Netherlands. Participants A humpback whale (Megaptera novaeangliae) and a laboratory mouse (Mus musculus). Main outcome measures Morphology and size of mesenchymal stem cells from adipose tissue. Results Morphologically, mesenchymal stem cells of the mouse and whale are indistinguishable. The average diameter of 50 mesenchymal stem cells from the mouse was 28 (SD 0.86) μm and 50 from the whale was 29 (SD 0.71) μm. The difference in cell size between the species was not statistically significant. Although the difference in bodyweight between the species is close to two million-fold, the mesenchymal stem cells of each were of similar size. Conclusions The mesenchymal stem cells of whales and mice are alike, in both morphology and size

The biological effects of IL-21 signaling on B-cell-mediated responses in organ transplantation

Antibody-mediated rejection has emerged as one of the major issues limiting the success of organ transplantation. It exerts a highly negative impact on graft function and outcome, and effective treatment is lacking. The triggers for antibody development, and the mechanisms leading to graft dysfunction and failure, are incompletely understood. The production of antibodies is dependent on instructions from various immunocytes including CD4 T-helper cells that secrete interleukin (IL)-21 and interact with antigen-specific B-cells via costimulatory molecules. In this article, we discuss the role of IL-21 in the activation and differentiation of B-cells and consider the mechanisms of IL-21 and B-cell interaction. An improved understanding of the biological mechanisms involved in antibody-mediated complications after organ transplantation could lead to the development of novel therapeutic strategies, which control humoral alloreactivity, potentially preventing and treating graft-threatening antibody-mediated rejection

Effect of arthritic synovial fluids on the expression of immunomodulatory factors by mesenchymal stem cells: An explorative in vitro study

Background:In diseased joints, the catabolic environment results in progressive joint damage. Mesenchymal stem cells (MSCs) can have immunomodulatory effects by secreting anti-inflammatory factors. To exert these effects, MSCs need to be triggered by proinflammatory cytokines. To explore the potential of MSCs as a treatment for diseased joints, we studied the effect of synovial fluid (SF) from donors with different joint diseases and donors without joint pathology on the immunomodulatory capacities of human MSCs in vitro. We hypothesized that SF of diseased joints influences the immunomodulatory effects of MSCs. Materials and Methods: MSCs were cultured in medium with SF of six osteoarthritis (OA) or six rheumatoid arthritis (RA) donors and three donors without joint pathology were used as control. Gene expressions of IL-6, HGF, TNFa, TGFb1, and indoleamine 2,3-dioxygenase (IDO) were analyzed. L-kynurenine concentration in conditioned medium (CM) by MSCs with SF was determined as a measure of IDO activity by MSCs. Furthermore, the effect of CM with SF on proliferation of activated lymphocytes was analyzed. Results: Addition of SF significantly up-regulated the mRNA expression of IL-6 and IDO in MSCs. SF(OA) induced significantly higher expression of IDO than SF(control), although no difference in IDO activity of the MSCs could be shown with a L-kynurenine assay. Medium conditioned by MSCs with SF(OA or RA) suppressed activated lymphocyte proliferation in vitro more than medium conditioned by MSCs without SF or with SF(control). Discussion: SF can influence the expression of genes involved in immunomodulation by MSCs and the effect on lymphocyte proliferation. We found indications for disease-specific differences between SFs but the variation between donors, even within one disease group was high. These data warrant further research to examine the potential application of MSC therapy in arthritic joints

Pre-Treatment of Human Mesenchymal Stem Cells with Inflammatory Factors or Hypoxia Does Not Influence Migration to Osteoarthritic Cartilage and Synovium

Background: Mesenchymal stem cells (MSCs) are promising candidates as a cell-based therapy for osteoarthritis (OA), although current results are modest. Pre-treatment of MSCs before application might improve their therapeutic efficacy. Hypothesis: Pre-treatment of MSCs with inflammatory factors or hypoxia will improve their migration and adhesion capacities toward OA-affected tissues. Study Design: Controlled laboratory study. Methods: We used real-time polymerase chain reaction to determine the effects of different fetal calf serum (FCS) batches, platelet lysate (PL), hypoxia, inflammatory factors, factors secreted by OA tissues, and OA synovial fluid (SF) on the expression of 12 genes encoding chemokine or adhesion receptors. Migration of MSCs toward factors secreted by OA tissues was studied in vitro, and attachment of injected MSCs was evaluated in vivo in healthy and OA knees of male Wistar rats. Results: Different FCS batches, PL, or hypoxia did not influence the expression of the migration and adhesion receptor genes. Exposure to inflammatory factors altered the expression of CCR1, CCR4, CD44, PDGFRα, and PDGFRβ. MSCs migrated toward factors secreted by OA tissues in vitro. Neither pre-treatment with inflammatory factors nor the presence of OA influenced MSC migration in vitro or adhesion in vivo. Conclusion: Factors secreted by OA tissues increase MSC migration in vitro. In vivo, no difference in MSC adhesion was found between OA and healthy knees. Pre-treatment with inflammatory factors influenced the expression of migration and adhesion receptors of MSCs but not their migration in vitro or adhesion in vivo. Clinical Relevance: To improve the therapeutic capacity of intra-articular injection of MSCs, they need to remain intra-articular for a longer period of time. Pre-treatment of MSCs with hypoxia or inflammatory factors did not increase the migration or adhesion capacity of MSCs and will therefore not likely prolong their intra-articular longevity. Alternative approaches to prolong the intra-articular presence of MSCs should be developed to increase the therapeutic effect of MSCs in OA

Are mesenchymal stromal cells immune cells?

Mesenchymal stromal cells (MSCs) are considered to be promising agents for the treatment of immunological disease. Although originally identified as precursor cells for mesenchymal lineages, in vitro studies have demonstrated that MSCs possess diverse immune regulatory capacities. Pre-clinical models have shown beneficial effects of MSCs in multiple immunological diseases and a number of phase 1/2 clinical trials carried out so far have reported signs of immune modulation after MSC infusion. These data indicate that MSCs play a central role in the immune response. This raises the academic question whether MSCs are immune cells or whether they are tissue precursor cells with immunoregulatory capacity. Correct understanding of the immunological properties and origin of MSCs will aid in the appropriate and safe use of the cells for clinical therapy. In this review the whole spectrum of immunological properties of MSCs is discussed with the aim of determining the position of MSCs in the immune system

Lysophosphatidic Acid Induces Migration of Human Lung‐Resident Mesenchymal Stem Cells Through the β‐Catenin Pathway

Mesenchymal stem cells (MSCs) have been demonstrated to reside in human adult organs. However, mechanisms of migration of these endogenous MSCs within their tissue of origin are not well understood. Here, we investigate migration of human adult lung‐resident (LR) mesenchymal progenitor cells. We demonstrate that bioactive lipid lysophosphatidic acid (LPA) plays a principal role in the migration of human LR‐MSCs through a signaling pathway involving LPA1‐induced β‐catenin activation. LR‐MSCs isolated from human lung allografts and lungs of patients with scleroderma demonstrated a robust migratory response to LPA in vitro. Furthermore, LPA levels correlated with LR‐MSC numbers in bronchoalveolar lavage (BAL), providing demonstration of the in vivo activity of LPA in human adult lungs. Migration of LR‐MSCs was mediated via LPA1 receptor ligation and LPA1 silencing significantly abrogated the migratory response of LR‐MSCs to LPA as well as human BAL. LPA treatment of LR‐MSCs induced protein kinase C‐mediated glycogen synthase kinase‐3β phosphorylation, with resulting cytoplasmic accumulation and nuclear translocation of β‐catenin. TCF/LEF dual luciferase gene reporter assay demonstrated a significant increase in transcriptional activity after LPA treatment. LR‐MSC migration and increase in reporter gene activity in the presence of LPA were abolished by transfection with β‐catenin small interfering RNA demonstrating that β‐catenin is critical in mediating LPA‐induced LR‐MSC migration. These data delineate a novel signaling pathway through which ligation of a G protein‐coupled receptor by a biologically relevant lipid mediator induces migration of human tissue‐resident mesenchymal progenitors. S tem C ells 2012;30:2010–2019Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93548/1/1171_ftp.pd

Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function

The immunomodulatory capacity of mesenchymal stem or stromal cells (MSC) makes them a promising tool for treatment of immune disease and organ transplantation. The effects of MSC on B cells are characterized by an abrogation of plasmablast formation and induction of regulatory B cells (Bregs). It is, however, unknown how MSC interact with B cells under inflammatory conditions. In this study, adipose tissue-derived MSC were pretreated with 50 ng/ml IFN-γ for 96 h (MSC-IFN-γ) to simulate inflammatory conditions. Mature B cells were obtained from spleens by CD43- selection. B cells were co-cultured with MSC and stimulated with anti-IgM, anti-CD40, and IL-2; and after 7 days, B cell proliferation, phenotype, Immunoglobulin-G (IgG), and IL-10 production were analyzed. MSC did not inhibit B cell proliferation but increased the percentage of CD38high CD24high B cells (Bregs) and IL-10 production, while MSC-IFN-γ significantly reduced B cell proliferation and inhibited IgG production by B cells in a more potent fashion but did not induce Bregs or IL-10 production. Both MSC and MSC-IFN-γ required proximity to target cells and being metabolically active to exert their effects. Indoleamine 2,3 dioxygenase expression was highly induced in MSC-IFN-γ and was responsible of the anti-proliferative and Breg reduction since addition of tryptophan (TRP) restored MSC properties. Immunological conditions dictate the effect of MSC on B cell function. Under immunological quiescent conditions, MSC stimulate Breg induction; whereas, under inflammatory conditions, MSC inhibit B cell proliferation and maturation through depletion of TRP. This knowledge is useful for customizing MSC therapy for specific purposes by appropriate pretreatment of MSC