Publications Page

Thank you for visiting our Publications Page.  This page will be updated with Merlin Publications and Related Publications throughout the duration of the MERLIN project.

Merlin Publications

Merlin project publications to date include the following:

Mouse mesenchymal stem cells inhibit high endothelial cell activation and lymphocyte homing to lymph nodes by releasing TIMP-1. Zanotti L, Angioni R, Calì B, Soldani C, Ploia C, Moalli F, Gargesha M, D’Amico G, Elliman S, Tedeschi G, Maffioli E, Negri A, Zacchigna S, Sarukhan A, Stein JV, Viola A . 

Leukemia May 2016:5 30(5):1143-54. DOI: 10.1038/leu.2016.33

Mesenchymal stem cells: myths and reality. Sarukhan A, Zanotti L, Viola A. 

Swiss Med Wkly. 2015;145:w14229. 23 Dec 2015. DOI: 10.4414/smw.2015.14229

Aging of bone marrow and umbilical cord derived mesenchymal stromal cells during expansion. Samantha de Witte, Eleonora E. Lambert, Ana Merino, Tanja Strini, Hannie J.C.W. Douben, Lisa O’Flynn, Steve J. Elliman, Annelies J.E.M.M. de Klein, Philip N. Newsome, Carla C. Baan and Martin J. Hoogduijn.

Cytotherapy 2017 (advance online corrected proof) DOI: 10.1016/j.jcyt.2017.03.071

Cytokine treatment optimises the immunotherapeutic effects of umbilical cord-derived MSC for treatment of inflammatory liver disease. Samantha F. H. de WitteEmail author, Ana M. Merino, Marcella Franquesa, Tanja Strini, Johanna A. A. van Zoggel, Sander S. Korevaar, Franka Luk, Madhu Gargesha, Lisa O’Flynn, Debashish Roy, Steve J. Elliman, Philip N. Newsome, Carla C. Baan and Martin J. Hoogduijn. 

Stem Cell Research & Therapy 20178:140 DOI: 10.1186/s13287-017-0590-6

Related Publications

This section includes other publications related to our work:

Are mesenchymal stromal cells immune cells?

Martin J Hoogduijn

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.

Human Adipose Tissue-Derived Mesenchymal Stem Cells Abrogate Plasmablast Formation and Induce Regulatory B Cells Independently of T Helper Cells

M. Franquesa*, F. K. Mensah, R. Huizinga, T. Strini, L. Boon, E. Lombardo, O. DelaRosa, J. D. Laman, J. M. Grinyó, W. Weimar, M. G. H. Betjes, C. C. Baan and M. J. Hoogduijn

Mesenchymal or stromal stem cells (MSC) interact with cells of the immune system in multiple ways. Modulation of the immune system by MSC is believed to be a therapeutic option for autoimmune disease and transplant rejection. In recent years, B cells have moved into the focus of the attention as targets for the treatment of immune disorders. Current B-cell targeting treatment is based on the indiscriminate depletion of B cells. The aim of this study was to examine whether human adipose tissue-derived MSC (ASC) interact with B cells to affect their proliferation, differentiation, and immune function. ASC supported the survival of quiescent B cells predominantly via contact-dependent mechanisms. Coculture of B cells with activated T helper cells led to proliferation and differentiation of B cells into CD19+CD27highCD38highantibody-producing plasmablasts. ASC inhibited the proliferation of B cells and this effect was dependent on the presence of T cells. In contrast, ASC directly targeted B-cell differentiation, independently of T cells. In the presence of ASC, plasmablast formation was reduced and IL-10-producing CD19+CD24highCD38high B cells, known as regulatory B cells, were induced. These results demonstrate that ASC affect B cell biology in vitro, suggesting that they can be a tool for the modulation of the B-cell response in immune disease. Stem Cells2015;33:880–891

No Evidence for Circulating Mesenchymal Stem Cells in Patients with Organ Injury

Martin J. Hoogduijn, Monique M.A. Verstegen, Anja U. Engela, Sander S. Korevaar, Marieke Roemeling-van Rhijn, Ana Merino, Marcella Franquesa, Jeroen de Jonge, Jan N. Ijzermans, Willem Weimar, Michiel G.H. Betjes, Carla C. Baan, and Luc J.W. van der Laan

Mesenchymal stem cells (MSC) are present in the bone marrow, from where they are thought to migrate through the blood stream to the sites of injury. However, virtually all tissues contain resident MSC that may contribute to local regenerative and immunomodulatory processes, thereby hypothetically preempting the need for recruiting MSC through the bloodstream. Although there is some indication for circulating MSC in animal models, there is little solid evidence for the mobilization and migration of MSC in the human circulation. In the present study, we were unable to detect MSC in the blood of healthy individuals. We then searched for MSC in the blood of ten patients with end-stage renal disease, ten patients with end-stage liver disease, and in eight heart transplant patients with biopsy-proven rejection by culturing of mononuclear cells under MSC-supporting culture conditions.

In none of these patient categories, MSC were identified in the blood. MSC were, however, found in the blood of a severe trauma patient with multiple fractures, suggesting that disruption of bone marrow leads to the release of MSC into the blood stream. The conclusion of this study is that MSC are not recruited into the circulation in patients with injured solid organs and during aggressive immune responses after transplantation.

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

Martin J Hoogduijn, Jooske Ijzer, Johanna C van den Beukel, Lidewij C M Wiersma

The class Mammalia contains species of extensively different phenotype and body size. The family Cetacea contains the largest mammals, whales. Cetaceans vary in body size, with the rare porpoise species vaquita (Phoeoena sinus) measuring 1.5m in length and with a bodyweight of 55 kg and the blue whale (Balaenoptera musculus)—the largest animal ever known to have lived—measuring up to 30 m in length and with a bodyweight of 180 000 kg. Mice (genus Mus) represent the other end of the mammalian size spectrum, with the common house mouse measuring about 8 cm in length, with a tail of approximately the same length, and a bodyweight on average of 20g.The common laboratory mouse (C57BL/6, or the “black  6” mouse) is of the same size and weight. Although organs are sized in proportion to the size of the animal, suborgan structures do not reflect this difference. For instance, capillaries in all mammals range from 5 to 10 μm, the optimal size for oxygen exchange. In recent decades interest in stem cells has been growing, from both a basic biological and a therapeutic perspective. In response to this, we compared the morphology and size of mesenchymal stem cells from two mammalian species of noticeably different body size.

Update on controls for isolation and quantification methodology of extracellular vesicles derived from adipose tissue mesenchymal stem cells

Marcella Franquesa, Juan Torras, Martin J. Hoogduijn, Carla C. Baan, Elia Ripoll, Franka Luk, Josep M. Grinyó, Ana Maria Merino, Mahdi Salih, Michiel G. H. Betjes

The research field on extracellular vesicles (EV) has rapidly expanded in recent years due to the therapeutic potential of EV. Adipose tissue human mesenchymal stem cells (ASC) may be a suitable source for therapeutic EV. A major limitation in the field is the lack of standardization of the challenging techniques to isolate and characterize EV.The aim of our study was to incorporate new controls for the detection and quantification of EV derived from ASC and to analyze the applicability and limitations of the available techniques. ASC were cultured in medium supplemented with 5% of vesicles-free fetal bovine serum.The EV were isolated from conditioned medium by differential centrifugation with size filtration (0.2μm). As a control, non-conditioned culture medium was used (control medium).To detect EV, electron microscopy, conventional flow cytometry, and western blot were used. The quantification of the EV was by total protein quantification, ExoELISA immunoassay, and Nanosight. Cytokines and growth factors in the EV samples were measured by multiplex bead array kit. The EV were detected by electron microscope. Total protein measurement was not useful to quantify EV as the control medium showed similar protein contents as the EV samples. The ExoELISA kits had technical troubles and it was not possible to quantify the concentration of exosomes in the samples. The use of Nanosight enabled quantification and size determination of the EV. It is, however, not possible to distinguish protein aggregates from EV with this method. The technologies for quantification and characterization of the EV need to be improved. In addition, we detected protein contaminants in the EV samples, which make it difficult to determine the real effect of EV in experimental models. It will be crucial in the future to optimize design novel methods for purification and characterization of EV.

Non-enzymatic dissociation of human mesenchymal stromal cells improves chemokine-dependent migration and maintains immunosuppressive function

Abhilok Garg, Diarmaid D. Houlihan, Victoria Aldridge, Shankar Suresh, Ka Kit Li, Andrew L. King, Rupesh Sutaria, Janine Fear, Ricky H. Bhogal, Patricia F. Lalor, Philip N. Newsome

Human bone marrow–derived mesenchymal stromal cells (MSC) can suppress inflammation; therefore their therapeutic potential is being explored in clinical trials. Poor engraftment of infused MSC limits their therapeutic utility; this may be caused by MSC processing before infusion, in particular the method of their detachment from culture.

This study demonstrates that non-enzymatic detachment of MSC with the use of CDB minimizes the negative impact on cell viability, multipotency and immunomodulation while retaining chemokine-dependent migration, which may be of importance in MSC delivery and engraftment in sites of injury.

Cytotherapy Volume 16, Issue 4, April 2014, Pages 545–559