Mesenchymal stromal cells Keating, Armand
Current opinion in hematology,
2006-November, Letnik:
13, Številka:
6
Journal Article
Odprti dostop
Our understanding of the biology and properties of mesenchymal stem cells or multipotent mesenchymal stromal cells has expanded dramatically over the last 3 years and is likely to have an impact on ...clinical practice in the near future, making a review of this topic both timely and relevant
Recommendations regarding nomenclature and the definition of mesenchymal stromal cells have been proposed, a rapidly dividing population within the mesenchymal stromal cell compartment has been better defined and the ability of these cells to exhibit characteristics of cells from a variety of lineages has been extended. The notion that tissue repair with mesenchymal stromal cells is related to transdifferentiation has been re-evaluated and, for the myocardium at least, may be due rather to a paracrine mechanism. The most dramatic developments have been in identifying some of the complex mechanisms underlying the immunosuppressive and nonimmunogenic properties of mesenchymal stromal cells which have important implications for the management of conditions like acute graft-versus-host disease.
Mesenchymal stromal cells are a biologically important cell population that are able to support hematopoiesis, can differentiate along mesenchymal and nonmesenchymal lineages in vitro, are capable of suppressing alloresponses and appear to be nonimmunogenic. These properties suggest emerging roles for mesenchymal stromal cells in cell therapy.
1 Human Anatomy, Department of Experimental Medicine, University of Genoa;
2 Centro Cellule Staminali e Terapia Cellulare, Ospedale San Martino, Genoa;
3 Histology Sections, Department of ...Experimental Medicine, University of Genoa;
4 Department of Translational Oncology and
5 Department of Otolaryngology, IST-National Cancer Research Institute, Genoa and
6 Department of Pediatric Hematology and Oncology, Ospedale Bambino Gesù, Rome, Italy
Correspondence: Franco Fais, Ph.D., Human Anatomy Section, Department of Experimental Medicine, Via De Toni, 14, 16132 Genoa, Italy, E-mail: franco.fais{at}unige.it
Background: CD1d is a monomorphic antigen presentation molecule expressed in several hematologic malignancies. Alpha-galactosylceramide ( -GalCer) is a glycolipid that can be presented to cytotoxic CD1d-restricted T cells. These reagents represent a potentially powerful tool for cell mediated immunotherapy.
Design and Methods: We set up an experimental model to evaluate the use of adoptively transferred cytotoxic CD1d-restricted T cells and -GalCer in the treatment of mice engrafted with CD1d + lymphoid neoplastic cells. To this end the C1R cell line was transfected with CD1c or CD1d molecules. In addition, upon retroviral infection firefly luciferase was expressed on C1R transfected cell lines allowing the evaluation of tumor growth in xenografted immunodeficient NOD/SCID mice.
Results: The C1R-CD1d cell line was highly susceptible to specific CD1d-restricted T cell cytotoxicity in the presence -GalCer in vitro . After adoptive transfer of CD1d-restricted T cells and -GalCer to mice engrafted with both C1R-CD1c and C1R-CD1d, a reduction in tumor growth was observed only in CD1d + masses. In addition, CD1d-restricted T-cell treatment plus -GalCer eradicated small C1R-CD1d + nodules. Immunohistochemical analysis revealed that infiltrating NKT cells were mainly observed in CD1d nodules.
Conclusions: Our results indicate that ex vivo expanded cytotoxic CD1d-restricted T cells and -GalCer may represent a new immunotherapeutic tool for treatment of CD1d + hematologic malignancies.
Key words: lymphoproliferative disorders, natural killer T cells, -galactosylceramide, CD1d, CD1d-restricted T cells.
Aging is a physiological process in which multifactorial processes determine a progressive decline. Several alterations contribute to the aging process, including telomere shortening, oxidative ...stress, deregulated autophagy and epigenetic modifications. In some cases, these alterations are so linked with the aging process that it is possible predict the age of a person on the basis of the modification of one specific pathway, as proposed by Horwath and his aging clock based on DNA methylation. Because the energy metabolism changes are involved in the aging process, in this work, we propose a new aging clock based on the modifications of glucose catabolism. The biochemical analyses were performed on mononuclear cells isolated from peripheral blood, obtained from a healthy population with an age between 5 and 106 years. In particular, we have evaluated the oxidative phosphorylation function and efficiency, the ATP/AMP ratio, the lactate dehydrogenase activity and the malondialdehyde content. Further, based on these biochemical markers, we developed a machine learning-based mathematical model able to predict the age of an individual with a mean absolute error of approximately 9.7 years. This mathematical model represents a new non-invasive tool to evaluate and define the age of individuals and could be used to evaluate the effects of drugs or other treatments on the early aging or the rejuvenation.
Many attempts have been made to improve the results of allogeneic bone marrow transplantation (alloBMT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). Bone marrow ...cell dose has been reported to be an important factor in alloBMT; however, its true impact on relapse incidence (RI), leukemia-free survival (LFS), and nonrelapse mortality (NRM) in a large cohort of patients is unknown.
From January 1992 to December 1999, 572 bone marrow transplantation recipients reported to the European Blood and Marrow Transplantation (EBMT) registry underwent allografting from an HLA-identical sibling donor with an unmanipulated bone marrow for AML in CR1.
The median number of nucleated cells (NCs) infused was 2.6 x 10(8)/kg. Estimated 5-year NRM, LFS, and RI for patients receiving more or less than 2.6 x 10(8) NCs/kg were, respectively, 18% +/- 5% v 30% +/- 5% (P =.001), 68% +/- 3% v 46% +/- 3% (P <.00001), and 14% +/- 4% v 24% +/- 5% (P =.004). The association of cell dose with the above outcomes was confirmed in multivariate analyses for NRM (relative risk RR, 0.53; P =.0007), for LFS (RR, 0.53; P =.00008), and for RI (RR, 0.57; P =.02). The cell dose was also an important factor for neutrophil (RR, 0.76; P =.009) and platelet (RR, 0.77; P =.03) recoveries; however, it did not statistically influence the incidence of acute graft-versus-host disease.
This study shows that marrow cell dose is one of the most important factors influencing relapse, NRM, and LFS after alloBMT for patients with AML in CR1. Therefore, increasing the marrow cell dose should substantially improve the survival of these patients.
We studied the immunoregulatory features of murine mesenchymal stem cells (MSCs) in vitro and in vivo. MSCs inhibited T-cell receptor (TCR)-dependent and -independent proliferation but did not induce ...apoptosis on T cells. Such inhibition was paired with a decreased interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha production and was partially reversed by interleukin-2 (IL-2). Thus, we used MSCs to treat myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice. We injected intravenously 1 × 106 MSCs before disease onset (preventive protocol) and at different time points after disease occurrence (therapeutic protocol). MSC administration before disease onset strikingly ameliorated EAE. The therapeutic scheme was effective when MSCs were administered at disease onset and at the peak of disease but not after disease stabilization. Central nervous system (CNS) pathology showed decreased inflammatory infiltrates and demyelination in mice that received transplants of MSCs. T-cell response to MOG and mitogens from MSC-treated mice was inhibited and restored by IL-2 administration. Upon MSC transfection with the enhanced green fluorescent protein (eGFP), eGFP+ cells were detected in the lymphoid organs of treated mice. These data suggest that the immunoregulatory properties of MSCs effectively interfere with the autoimmune attack in the course of EAE inducing an in vivo state of T-cell unresponsiveness occurring within secondary lymphoid organs. (Blood. 2005; 106:1755-1761)
Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we ...assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft.
Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites.
The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively.
UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.
Abstract Blood stream infections (BSI) are a well-known cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients. The aim of this study was to analyze etiology and ...microbial resistance of BSI in patients undergoing allogeneic HSCT in a single center over a 4-year period (2004-2007). There were 168 episodes of BSI in 132 patients (median 10 days after HSCT) and 182 pathogens were isolated. Gram-positive bacteria (GPB) accounted for 57% of 182 isolates. Gram-negative rods (GNR) for 37% and fungi for 6%. All patients received routine fluoroquinolone prophylaxis. There was a significant decrease in GPB/GNR ratio over time, from 2.4 in 2004 to 1 in 2007 ( P = .043). Among GPB, staphylococci decreased from 37 of 68 (64%) in 2004-2005 to 8 of 35 (23%) in 2006-2007 ( P < .002). The Enterococcus faecalis/E. faecium ratio decreased from 4.5 in 2004 to 0.33 in 2007 ( P = .006), whereas the total number of enterococcal strains per year did not change. The incidence of Escherichia coli among GNR increased from 3 of 15 (20%) in 2004 to 13 of 21 (62%) in 2007 ( P = .003). Fluoroquinolone-resistance was common, both among GPB and GNR (81% and 74%, respectively). Mortality rate at 7 days after BSI was 11% (19 of 168), reaching 39% for Pseudomonas aeruginosa BSI (7 of 18). BSI remains a frequent and potentially life-threatening complication of allogeneic HSCT, the causative organism influencing 7- and 30-day mortality rate. BSI etiology may change rapidly, requiring implementation of new empirical-therapy schemes.
Summary
Mesenchymal stromal cell (MSC) infusions have been reported to be effective in patients with steroid‐refractory, acute graft‐versus‐host disease (aGvHD) but comprehensive data on paediatric ...patients are limited. We retrospectively analysed a cohort of 37 children (aged 3 months‐17 years) treated with MSCs for steroid‐refractory grade III–IV aGvHD. All patients but three received multiple MSC infusions. Complete response (CR) was observed in 24 children (65%), while 13 children had either partial (n = 8) or no response (n = 5). Cumulative incidence of transplantation‐related mortality (TRM) in patients who did or did not achieve CR was 17% and 69%, respectively (P = 0·001). After a median follow‐up of 2·9 years, overall survival (OS) was 37%; it was 65% vs. 0% in patients who did or did not achieve CR, respectively (P = 0·001). The median time from starting steroids for GvHD treatment to first MSC infusion was 13 d (range 5–85). Children treated between 5 and 12 d after steroid initiation showed a trend for better OS (56%) and lower TRM (17%) as compared with patients receiving MSCs 13–85 d after steroids (25% and 53%, respectively; P = 0·22 and 0·06, respectively). Multiple MSC infusions are safe and effective for children with steroid‐refractory aGvHD, especially when employed early in the disease course.
Abstract The outcome of umbilical cord blood transplantation for adult patients with hematologic malignancies now rivals that of matched unrelated donor transplantation. However, relatively low ...lymphocyte and hematopoietic stem and progenitor cell dose is a source of significant morbidity and mortality. Multiple strategies are now being studied to overcome these limitations. One strategy involves ex vivo expansion of the umbilical cord blood unit before transplantation. Ex vivo expansion has the potential to increase the number of lymphocytes, committed progenitors and long-term repopulating hematopoietic stem cells. Increasing the numbers of lymphocytes and committed progenitor cells will address the issue of delayed hematopoietic recovery after umbilical cord blood transplantation. Increasing the hematopoietic stem cell content will improve the availability of adequately sized and matched cord blood units for transplantation. It may also eliminate the need for dual umbilical cord blood transplantation for those without an adequately sized single umbilical cord blood graft. The second strategy involves exposure of the umbilical cord blood graft to compounds aimed at improving homing and engraftment following transplantation. Such a strategy may also address the problem of slow hematopoietic recovery as well as the increased risk of graft failure. Many of these strategies are now being tested in late-phase multi-center clinical trials. If proven cost-effective and efficacious, they may alter the landscape of donor options for allogeneic stem cell transplantation.
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