grupo

Group name: Stromal Cell and Immunology Group

    Group leader
  • Per Anderson
  • PHD Students
  • Ana Belén Carrillo Gálvez

SCIENTIFIC INTEREST AREAS

Mesenchymal stromal cells (MSCs) have received much attention due to their promise as a treatment in regenerative medicine and autoimmune disease but also due to their emerging role as important modulators of cancer growth and invasiveness. Our group is interested in understanding the role of MSCs in health and disease and their use as a therapy for human inflammatory/autoimmune diseases. We are currently focusing on (i) analyzing the heterogeneity of MSC preparations and its impact on their therapeutic efficacy; (ii) understanding the immunomodulatory capacity of MSCs and (iii) investigating the role of TGF-β1/GARP in MSC biology and cancer.

RESEARCH AREAS

1. Analysis of the heterogeneity of MSC preparations

MSCs cultures contain phenotypically and functionally distinct cell types. This heterogeneity impairs their therapeutic efficacy and endorses variability between experiments. The objective of this particular line of investigation is to further characterize MSC preparations from different tissues with the aim of designing more efficient and specific MSC-based therapies. We have recently found that murine MSCs from adipose tissue (mASCs) are heterogeneous for endoglin (CD105) expression. The CD105+ and CD105- mMSC subpopulations had similar growth potential and expressed identical MSC markers but varied in their differentiation and immunoregulatory properties (Anderson et al., PLOS ONE 2013).

2. Understanding how MSCs modulate the immune response

MSCs are potent modulators of the immune system both in vitro and in vivo and it is important to understand their immunomodulatory properties in order to maximize their therapeutic potential. We are investigating how MSCs interact with cells of the immune system, trying to identify novel mechanisms of MSC-mediated immunomodulation. We have thus far found that murine and human ASCs, via PGE2, can induce regulatory macrophages (MΦregs) in vitro. These MΦregs expressed high levels of arginase I and interleukin-10 and ameliorated both experimental colitis and sepsis (Anderson et al., Gut 2013). In another study we showed that mASCs inhibit T cell proliferation and dendritic cell function in vitro. Administration of mASCs to mice suffering from experimental autoimmune encephalomyelitis, a well known model of human multiple sclerosis, reduced T cell and dendritic cell activation and ameliorated the inflammation/destruction of the central nervous system (Manuscript in preparation).

3. The role of Glycoprotein A repetitions predominant (GARP) in MSC biology

TGF-β1 is a pleiotropic cytokine and a key molecule in development, immunity and cancer. TGF-β1 is produced by MSCs and has been demonstrated to promote fibroblast proliferation and to participate in MSC-mediated immunomodulation. We recently showed that MSCs express GARP, also known as leucine rich repeat containing 32 (LRRC32) on their surface. We found that GARP binds TGF-β1 to the surface of the MSCs, regulating the secretion/activation of TGF-β1. We also found that GARP affects the proliferation and immunomodulatory capacity of MSCs (Carrillo-Gálvez et al., Stem Cells 2015). We are now continuing our study on GARP/LRRC32 and MSCs focusing on:

(1) GARP as a marker for activated MSCs in vivo. We found that GARP is rapidly induced on both murine and human MSCs upon culture in vitro. We believe that GARP is induced on MSCs upon activation and could thus serve as a novel marker for in vivo activated MSCs.

(2) GARP and proliferation. GARP appears to be important for the proliferative activity of MSCs, T cells and some tumor cell lines. However, it is not known how GARP can control cell proliferation, especially MSC proliferation. We are currently over-expressing or silencing GARP in MSCs and analyzing their cell cycle progression, expression of cell cycle inhibitors, apoptosis, cell senescence and gene expression profile using microarray.

4. The role of MSCs and GARP in cancer

Apart from the great interest in MSCs as a cell therapy for inflammatory/autoimmune diseases, recent studies have identified an important role of MSCs in cancer. Both endogenous and exogenously administrated MSCs can migrate towards tumors, participate in the tumor niche and promote tumor growth and metastasis through differentiation into tumor-promoting myofibroblasts and by the expression of growth factors/ immunomodulatory cytokines that can (i) promote angiogenesis and tumor growth, (ii) suppress anti-cancer immune responses and (iii) induce epithelial to mesenchymal transition (EMT) in cancer cells. We aim to study (1) the role of GARP/TGF-β1 in the MSC-mediated promotion of cancer and (2) the possible involvement of GARP in endothelial function/angiogenesis and cancer cell proliferation/survival.

FUNDING

ID: PI15/00794

PROJECT TITLE: Papel de la glicoproteina A predominante en repeticiones (GARP) en Cáncer

FINANCIAL ENTITY: INSTITUTO DE SALUD CARLOS III

PRINCIPAL INVESTIGATOR: PER ANDERSON

LENGTH: FROM: 01/01/2016 TO: 31/12/2018

FUNDING: 122.815€

 

ID: PI12/01390

PROJECT TITLE: Mesenchymal stromal cells as a tool for the treatment of inflammatory/autoimmune diseases: role of transforming growth factor (TGF)-beta

FINANCIAL ENTITY: INSTITUTO DE SALUD CARLOS III

PRINCIPAL INVESTIGATOR: PER ANDERSON

LENGTH: FROM: 01/01/2013 TO: 01/01/2016

FUNDING: 150.645€

 

ID: CP09/00228

PROJECT TITLE: Phenotypic and functional characterization of adipose-derived mesenchymal stem cells for the treatment of autoimmune disease

FINANCIAL ENTITY: INSTITUTO DE SALUD CARLOS III

PRINCIPAL INVESTIGATOR: PER ANDERSON

LENGTH: FROM: 01/02/2010 TO: 01/02/2016

FUNDING: 45.000€

SELECTED PUBLICATIONS

Carrillo-Gálvez AB, Cobo M, Cuevas-Ocaña S, Gutiérrez-Guerrero A, Sánchez-Gilabert A, Bongarzone P, García-Pérez A, Muñoz P, Benabdellah K, Toscano MG, Martin F, Anderson P. Mesenchymal stromal cells express GARP/LRRC32 on their surface: Effects on their biology and immunomodulatory capacity. Stem Cells 2015; Jan; (33:1), pp.183-195.                               

Anderson P, Carrillo-Gálvez A, García-Pérez A, Cobo M, Martin F. CD105 (Endoglin)-Negative Murine Mesenchymal Stromal Cells Define a New Multipotent Subpopulation with Distinct Differentiation and Immunomodulatory Capacities. PLOS ONE 2013; Oct 4;8(10):e76979.                                      

Toscano MG, Anderson P, Muñoz P, Lucena G, Cobo M, Benabdellah K, Gregory PD, Holmes M and Martín F. WASP-deficient K562 cells mimic megakaryocytic-related defects from Wiskott-Aldrich syndrome patients. Dis Model Mech 2013; Vol 6, pp.544-54.                                             

Cobo M*, Anderson P*, Benabdellah K, Toscano M, Muñoz P, Gutierrez I, Delgado M, Martin F (*Shared authorship). Gene-cell therapies for a severe model of chronic multiple sclerosis. Cell Transplantation (2013); Vol 22, pp.839-54. *Shared authorship.

Anderson P, Moreira L, Morell M, Caro M, O´Valle F, Gonzalez-Rey E, Delgado M Adipose tissue-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis. Gut (2013); Vol 62, pp.1131-41.

Muñoz P, Toscano MG, Real PJ, Benabdellah K, Cobo M, Bueno C, Ramos-Mejía V, Menendez P, Anderson P, Martín F. Specific marking of hESCs-derived hematopoietic lineage by WAS-promoter driven lentiviral vectorsPLOS ONE (2012); Vol 7(6):e39091.                                              

Ramos-Mejía V, Fernández AF, Ayllón V, Real PJ, Bueno C, Anderson P, Martín F, Fraga, MF, Menendez P. Maintenance of hESCs in mesenchymal stem cell-conditioned media augments hematopoietic specification. Stem Cells and Development (2012); Vol 21, pp.1549-58.       

Stenström MAnderson P, Eroukhmanoff L, Leanderson T, Ivars F. Selective depletion of splenic CD4 dendritic cells in mice treated with immunomodulatory quinoline-3 carboxamide ABR-215757. International Immunopharmacology (2010)Vol 10, pp.837-842. 

Anderson P and Gonzalez-Rey E. Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels. Molecular and Cellular Biology (2010)Vol 30, pp.2537-2551.    

Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado, M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut (2009), Vol. 58 pp.929-939.

RESEARCH GROUP PATENTS

(1) N. de registro: EP13382338.5

YEAR: 2013

TITLE: CD105-negative multipotent mesenchymal stromal cells

AUTHORS: Per Anderson, Francisco Martin, Ana Belen Carrillo-Gálvez, Marién Cobo

Entidad Titular. Fundación progreso y Salud (FPS)

 

(2) N. de registro: P201331730

YEAR: 2013

TITLE: Nuevo marcador de superficie de células madre mesenquimales

AUTHORS: Per Anderson, Francisco Martin, Ana Belen Carrillo-Gálvez, Marién Cobo, Angélica García-Pérez

Entidad Titular. Fundación progreso y Salud (FPS)