In addition to their stem/progenitor properties, mesenchymal stromal cells (MSCs) possess broad immunoregulatory properties that are being investigated for potential clinical application in treating ...immune-based disorders. An informed view of the scope of this clinical potential will require a clear understanding of the dynamic interplay between MSCs and the innate and adaptive immune systems. In this Review, we outline current insights into the ways in which MSCs sense and control inflammation, highlighting the central role of macrophage polarization. We also draw attention to functional differences seen between vivo and in vitro contexts and between species. Finally, we discuss progress toward clinical application of MSCs, focusing on GvHD as a case study.
This Review discusses the role of MSCs in sensing and controlling inflammation, highlighting the central role of macrophage polarization, differences based on species and physiological contexts, and potential clinical applications.
The most common cause of treatment failure in childhood acute lymphoblastic leukemia (ALL) remains relapse, occurring in ∼ 15%-20% of patients. Survival of relapsed patients can be predicted by site ...of relapse, length of first complete remission, and immunophenotype of relapsed ALL. BM and early relapse (< 30 months from diagnosis), as well as T-ALL, are associated with worse prognosis than isolated extramedullary or late relapse (> 30 months from diagnosis). In addition, persistence of minimal residual disease (MRD) at the end of induction or consolidation therapy predicts poor outcome because children with detectable MRD are more likely to relapse than those in molecular remission, even after allogeneic hematopoietic stem cell transplantation. We offer hematopoietic stem cell transplantation to any child with high-risk features because these patients are virtually incurable with chemotherapy alone. By contrast, we treat children with first late BM relapse of B-cell precursor ALL and good clearance of MRD with a chemotherapy approach. We use both systemic and local treatment for extramedullary relapse, mainly represented by radiotherapy and, in case of testicular involvement, by orchiectomy. Innovative approaches, including new agents or strategies of immunotherapy, are under investigation in trials enrolling patients with resistant or more advanced disease.
Mesenchymal stem cells (MSCs) were first isolated more than 50 years ago from the bone marrow. Currently MSCs may also be isolated from several alternative sources and they have been used in more ...than a hundred clinical trials worldwide to treat a wide variety of diseases. The MSCs mechanism of action is undefined and currently under investigation. For in vivo purposes MSCs must be produced in compliance with good manufacturing practices and this has stimulated research on MSCs characterization and safety. The objective of this review is to describe recent developments regarding MSCs properties, physiological effects, delivery, clinical applications and possible side effects.
Sixty thalassemia patients (median age, 7 years; range, 1-37) underwent allogeneic hematopoietic stem cell transplantation (HSCT) after a preparation combining thiotepa, treosulfan, and fludarabine. ...Before HSCT, 27 children were assigned to risk class 1 of the Pesaro classification, 17 to class 2, and 4 to class 3; 12 patients were adults. Twenty patients were transplanted from an HLA-identical sibling and 40 from an unrelated donor. The cumulative incidence of graft failure and transplantation-related mortality was 9% and 7%, respectively. Eight patients experienced grade II-IV acute GVHD, the cumulative incidence being 14%. Among 56 patients at risk, 1 developed limited chronic GVHD. With a median follow-up of 36 months (range, 4-72), the 5-year probability of survival and thalassemia-free survival are 93% and 84%, respectively. Neither the class of risk nor the donor used influenced outcome. This treosulfan-based preparation proved to be safe and effective for thalassemia patients given allogeneic HSCT.
Mesenchymal stromal cells (MSCs) are key elements in the bone marrow (BM) niche where they interact with hematopoietic stem progenitor cells (HSPCs) by offering physical support and secreting soluble ...factors, which control HSPC maintenance and fate. Although necessary for their maintenance, MSCs are a rare population in the BM, they are plastic adherent and can be ex vivo expanded to reach numbers adequate for clinical use. In light of HSPC supportive properties, MSCs have been employed in phase I/II clinical trials of hematopoietic stem cell transplantation (HSCT) to facilitate engraftment of hematopoietic stem cells (HSCs). Moreover, they have been utilized to expand ex vivo HSCs before clinical use. The available clinical evidence from these trials indicate that MSC administration is safe, as no acute and long‐term adverse events have been registered in treated patients, and may be efficacious in promoting hematopoietic engraftment after HSCT. In this review, we critically discuss the role of MSCs as component of the BM niche, as recent advances in defining different mesenchymal populations in the BM have considerably increased our understanding of this complex environment. Moreover, we will revise published literature on the use of MSCs to support HSC engraftment and expansion, as well as consider potential new MSC application in the clinical context of ex vivo gene therapy with autologous HSC.
Mesenchymal stromal cells (MSCs) are being employed in clinical trials to facilitate engraftment and to treat steroid‐resistant acute graft‐versus‐host disease after hematopoietic stem cell ...transplantation, as well as to repair tissue damage in inflammatory/degenerative disorders, in particular, in inflammatory bowel diseases (IBDs). When entering the clinical arena, a few potential risks of MSC therapy have to be taken into account: (i) immunogenicity of the cells, (ii) biosafety of medium components, (iii) risk of ectopic tissue formation, and (iv) potential in vitro transformation of the cells during expansion. This paper analyzes the main risks connected with the use of MSCs in cellular therapy approaches, and reports on some of the most intriguing findings on the use of MSCs in the context of regenerative medicine. Experimental studies in animal models and phase I/II clinical trials on the use of MSCs for the treatment of IBDs and other inflammatory/degenerative conditions are reviewed.
Hematopoietic stem and progenitor cells (HSPC) reside in the bone marrow (BM) niche and serve as a reservoir for mature blood cells throughout life. Aging in the BM is characterized by low‐grade ...chronic inflammation that could contribute to the reduced functionality of aged HSPC. Mesenchymal stromal cells (MSC) in the BM support HSPC self‐renewal. However, changes in MSC function with age and the crosstalk between MSC and HSPC remain understudied. Here, we conducted an extensive characterization of senescence features in BM‐derived MSC from young and aged healthy donors. Aged MSC displayed an enlarged senescent‐like morphology, a delayed clonogenic potential and reduced proliferation ability when compared to younger counterparts. Of note, the observed proliferation delay was associated with increased levels of SA‐β‐galactosidase (SA‐β‐Gal) and lipofuscin in aged MSC at early passages and a modest but consistent accumulation of physical DNA damage and DNA damage response (DDR) activation. Consistent with the establishment of a senescence‐like state in aged MSC, we detected an increase in pro‐inflammatory senescence‐associated secretory phenotype (SASP) factors, both at the transcript and protein levels. Conversely, the immunomodulatory properties of aged MSC were significantly reduced. Importantly, exposure of young HSPC to factors secreted by aged MSC induced pro‐inflammatory genes in HSPC and impaired HSPC clonogenic potential in a SASP‐dependent manner. Altogether, our results reveal that BM‐derived MSC from aged healthy donors display features of senescence and that, during aging, MSC‐associated secretomes contribute to activate an inflammatory transcriptional program in HSPC that may ultimately impair their functionality.
Aged mesenchymal stromal cells (MSC) display early senescence features including SA‐β‐Gal accumulation, DDR, and SASP activation. Through SASP, aged MSC impair the clonogenic potential of hematopoietic stem and progenitor cells (HSPC) and induce the activation of a pro‐inflammatory transcriptional program in young HSPC.
Lysosomal storage diseases (LSDs) are rare inherited metabolic disorders characterized by a dysfunction in lysosomes, leading to waste material accumulation and severe organ damage. Enzyme ...replacement therapy (ERT) and haematopoietic stem cell transplant (HSCT) have been exploited as potential treatments for LSDs but pre-clinical and clinical studies have shown in some cases limited efficacy. Intravenous ERT is able to control the damage of visceral organs but cannot prevent nervous impairment. Depending on the disease type, HSCT has important limitations when performed for early variants, unless treatment occurs before disease onset. In the attempt to overcome these issues, gene therapy has been proposed as a valuable therapeutic option, either ex vivo, with target cells genetically modified in vitro, or in vivo, by inserting the genetic material with systemic or intra-parenchymal, in situ administration. In particular, the use of autologous haematopoietic stem cells (HSC) transduced with a viral vector containing a healthy copy of the mutated gene would allow supra-normal production of the defective enzyme and cross correction of target cells in multiple tissues, including the central nervous system. This review will provide an overview of the most recent scientific advances in HSC-based gene therapy approaches for the treatment of LSDs with particular focus on metachromatic leukodystrophy (MLD) and mucopolysaccharidosis type I (MPS-I).
Summary Background Severe graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic transplantation with haemopoietic stem cells. Mesenchymal stem cells modulate immune ...responses in vitro and in vivo. We aimed to assess whether mesenchymal stem cells could ameliorate GVHD after haemopoietic-stem-cell transplantation. Methods Patients with steroid-resistant, severe, acute GVHD were treated with mesenchymal stem cells, derived with the European Group for Blood and Marrow Transplantation ex-vivo expansion procedure, in a multicentre, phase II experimental study. We recorded response, transplantation-related deaths, and other adverse events for up to 60 months' follow-up from infusion of the cells. Findings Between October, 2001, and January, 2007, 55 patients were treated. The median dose of bone-marrow derived mesenchymal stem cells was 1·4×106 (min–max range 0·4–9×106 ) cells per kg bodyweight. 27 patients received one dose, 22 received two doses, and six three to five doses of cells obtained from HLA-identical sibling donors (n=5), haploidentical donors (n=18), and third-party HLA-mismatched donors (n=69). 30 patients had a complete response and nine showed improvement. No patients had side-effects during or immediately after infusions of mesenchymal stem cells. Response rate was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. Complete responders had lower transplantation-related mortality 1 year after infusion than did patients with partial or no response (11 37% of 30 vs 18 72% of 25; p=0·002) and higher overall survival 2 years after haemopoietic-stem-cell transplantation (16 53% of 30 vs four 16% of 25; p=0·018). Interpretation Infusion of mesenchymal stem cells expanded in vitro, irrespective of the donor, might be an effective therapy for patients with steroid-resistant, acute GVHD. Funding Swedish Cancer Society, Children's Cancer Foundation, Swedish Research Council, Cancer Society in Stockholm, Cancer and Allergy Foundation, Karolinska Institutet, Istituto Superiore di Sanità, European Union, Regione Lombardia, Fondazione CARIPLO, Associazione Italiana Ricerca contro il Cancro, Compagnia di San Paolo Torino, Progetto CARIGE Cellule Staminali, European Commission, Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Ricerca Finalizzata Regione Liguria 2005 Assistenza Domiciliare, Dutch Programme for Tissue Engineering.
We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)–like receptors (KIR) ligand-mismatched donors. We ...showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1+ NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3+ NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3+ (or by NKG2A+) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.
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