Papers by Annalisa Pasini
Haematologica, 2006
A flow cytometric approach to minimal residual disease (MRD) monitoring useful in childhood B-lin... more A flow cytometric approach to minimal residual disease (MRD) monitoring useful in childhood B-lineage acute lymphoblastic leukemia (ALL) is discussed here in the context of ALL in adults. Of 64 leukemia samples analyzed, 95.3% had at least one abnormal phenotype (57.3% had two or more) as compared to physiologic B-cell precursors in adult bone marrow. The method was sensitive enough to detect one leukemic cell among 10,000 normal cells in 16/19 experiments (84.2%). Blast phenotypes were stable in culture and at relapse, and were useful for MRD monitoring in patients. Marker combinations for childhood ALL are also applicable to adult cases.
Advances in Stem Cell Research, 2012
Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, ... more Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory.
Transfusion Medicine and Hemotherapy, 2008
SUMMARY: Mesenchymal stem cells (MSCs) and their stromal progeny may be considered powerful regul... more SUMMARY: Mesenchymal stem cells (MSCs) and their stromal progeny may be considered powerful regulatory cells, a sort of dendritic cell counterpart, which influence all the main immune effectors and functional roles in vivo, as well as potential applications in the treatment of a number of human immunological diseases. By choosing MSC tissue origen, cell dose, administration route, and treatment schedule, all the potential side effects related to MSC use, including tumor growth enhancement, have to be well considered to maximize the benefits of MSC-depen-dent immune regulation without significant risks for the patients.
Stem Cells, 2008
are multipotent, nonhemopoietic progenitors that also possess regulatory activity on immune effec... more are multipotent, nonhemopoietic progenitors that also possess regulatory activity on immune effector cells through different mechanisms. We demonstrate that human BMderived MSCs expressed high levels of Toll-like receptors (TLRs) 3 and 4, which are both functional, as shown by the ability of their ligands to induce nuclear factor B (NF-B) activity, as well as the production of interleukin (IL)-6, IL-8, and CXCL10. Of note, ligation of TLR3 and TLR4 on MSCs also inhibited the ability of these cells to suppress the proliferation of T cells, without influencing their immunophenotype or differentiation potential. The TLR triggering effects appeared to be related to the impairment of MSC
Stem Cells, 2006
HLA-unrelated T lymphocytes to allogeneic stimulation, but the mechanisms responsible for this ac... more HLA-unrelated T lymphocytes to allogeneic stimulation, but the mechanisms responsible for this activity are not fully understood. We show here that MSCs suppress the proliferation of both CD4 ؉ and CD8 ؉ T lymphocytes, as well as of natural killer (NK) cells, whereas they do not have an effect on the proliferation of B lymphocytes. The antiproliferative effect of MSCs was not associated with any effect on the expression of cell-activation markers, induction of cell apoptosis, or mimicry/enhancement of T regulatory cell activity. The suppressive activity of MSCs was not contactdependent and required the presence of interferon (IFN)-␥ produced by activated T cells and NK cells. Accordingly, even activated B cells became susceptible to the suppressive activity of MSCs in the presence of exogenously added IFN-␥. The suppressive effect of IFN-␥ was related to its ability to stimulate the production by MSCs of indoleamine 2,3-dioxygenase activity, which in turn inhibited the proliferation of activated T or NK cells. These findings suggest that the beneficial effect on graft-versus-host disease induced by in vivo coinfusion with the graft of MSCs may be due to the activation of the immunomodulatory properties of MSCs by T cell-derived IFN-␥. STEM CELLS 2006;24: 386 -398
Plastic and Reconstructive Surgery, 2007
Experimental Cell Research, 2008
It has recently been shown that adipose tissue is an abundant and easily accessible source of str... more It has recently been shown that adipose tissue is an abundant and easily accessible source of stromal progenitor cells (ADSCs, adipose-derived stromal cells), resembling the mesenchymal stem cells (MSCs) obtained from adult bone marrow. However, the identification of these two lineages is still controversial and even the stem cell nature of ADSCs is doubted. In this study, we examined the "stemness" transcriptional profile of ADSCs and BM-MSCs, with two aims: (1) to compare their "stem cell molecular signature" and (2) to dissect their constitutive expression pattern for molecules involved in tissue development, homeostasis and repair. As well as several molecules involved in matrix remodeling and adult tissue angiogenesis and repair, we detected the expression of genes UTF-1, Nodal, and Snail2, which are known to be expressed by embryonic stem cells but have been never described in other stem lineages. In addition, for the first time we described the transcriptional profile of human BM-MSCs and ADSCs for the CD44 splice variants, which are determinant in cell trafficking during embryonic development, in adult tissue homeostasis and also in tumor dissemination.
Current Opinion in Pharmacology, 2006
Bone, 2007
Mesenchymal stem cells (MSCs) from bone marrow (BM) and sub-cutaneous fat are known to differenti... more Mesenchymal stem cells (MSCs) from bone marrow (BM) and sub-cutaneous fat are known to differentiate into neural cells under appropriate stimuli. We describe here the neural-like differentiation of human MSCs obtained from spleen and thymus, induced either with chemical factors or with co-culture with human Schwann cells (Sc). Under the effect of neural differentiation medium, most MSCs from BM, fat, spleen and thymus acquired morphological changes suggestive of cells of astrocytic/neuronal and oligodendroglial lineages with general up-regulation of neural molecules not correlated with morphological changes. The process was transient and reversible, as MSCs recovered basal morphology and phenotype, as well as their multilineage differentiation potential. Thus, we hypothesized that chemical factors may prime MSCs for neural differentiation, by inducing initial and poorly specific changes. By contrast, co-cultures of MSCs of different origen with Sc induced long-lasting and Sc differentiation, i.e., the expression of Sc myelin proteins for up to 12 days. Our results show that a MSC reservoir is present in tissues other than BM and fat, and that MSCs of different origen have similar neural differentiation potential. This evidence provides new insights into BM-like tissue plasticity and may have important implications for future therapeutic interventions in chronic neuropathies.
Stem Cells and Development, 2007
We show here that human and mouse mesenchymal stem cells (MSCs) can be obtained not only from bon... more We show here that human and mouse mesenchymal stem cells (MSCs) can be obtained not only from bone marrow (BM), but also from adult spleen and thymus. In vitro, both human and mouse spleen- and thymus-derived MSCs exhibit immunophenotypic characteristics and differentiation potential completely comparable to BM-MSCs. In addition, they can inhibit immune responses mediated by activated T lymphocytes with efficiency comparable to BM-MSCs. In vivo, mouse MSCs from BM, spleen, and thymus, if injected together with a genetically modified tumor cell vaccine, can equally prevent the onset of an anti-tumor memory immune response, thus leading to tumor growth in normally resistant mice. Our data suggest that not only do spleen and thymus have a stem cell reservoir to build up their stromal architecture, but also contain microenviromental immunoregulatory cells with the same properties of BM-MSCs.
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Papers by Annalisa Pasini