Publications by authors named "Francesco Dazzi"

95 Publications

Immunomodulatory Properties of Mesenchymal Stromal Cells: An Update.

Front Cell Dev Biol 2021 9;9:637725. Epub 2021 Feb 9.

Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.

Mesenchymal stromal cells (MSCs) are characterized by an extraordinary capacity to modulate the phenotype and functional properties of various immune cells that play an essential role in the pathogenesis of inflammatory disorders. Thus, MSCs efficiently impair the phagocytic and antigen-presenting capacity of monocytes/macrophages and promote the expression of immunosuppressive molecules such as interleukin (IL)-10 and programmed cell death 1 ligand 1 by these cells. They also effectively inhibit the maturation of dendritic cells and their ability to produce proinflammatory cytokines and to stimulate potent T-cell responses. Furthermore, MSCs inhibit the generation and proinflammatory properties of CD4 T helper (Th)1 and Th17 cells, while they promote the proliferation of regulatory T cells and their inhibitory capabilities. MSCs also impair the expansion, cytokine secretion, and cytotoxic activity of proinflammatory CD8 T cells. Moreover, MSCs inhibit the differentiation, proliferation, and antibody secretion of B cells, and foster the generation of IL-10-producing regulatory B cells. Various cell membrane-associated and soluble molecules essentially contribute to these MSC-mediated effects on important cellular components of innate and adaptive immunity. Due to their immunosuppressive properties, MSCs have emerged as promising tools for the treatment of inflammatory disorders such as acute graft-versus-host disease, graft rejection in patients undergoing organ/cell transplantation, and autoimmune diseases.
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http://dx.doi.org/10.3389/fcell.2021.637725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900158PMC
February 2021

Persistence of Drug-Resistant Leukemic Stem Cells and Impaired NK Cell Immunity in CML Patients Depend on Antiproliferative and PP2A-Activating Functions.

Blood Cancer Discov 2020 Jul;1(1):48-67

Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.

Persistence of drug-resistant quiescent leukemic stem cells (LSC) and impaired natural killer (NK) cell immune response account for relapse of chronic myelogenous leukemia (CML). Inactivation of protein phosphatase 2A (PP2A) is essential for CML-quiescent LSC survival and NK cell antitumor activity. Here we show that has antiproliferative and PP2A-activating functions that are dose dependently differentially induced by CCND2/CDK6 and SET inhibition, respectively. is upregulated in CML LSCs and NK cells by bone marrow microenvironment (BMM) signals to induce quiescence and impair immune response, respectively. Conversely, BCR-ABL1 downregulates in CML progenitors to prevent growth arrest and PP2A-mediated apoptosis. Quiescent LSCs escape apoptosis by upregulating long noncoding RNA that uncouples and limits function to cytostasis. Genetic and pharmacologic modulation and/or PP2A-activating drug treatment restore NK cell activity, inhibit BMM-induced growth arrest, and selectively trigger LSC apoptosis and in patient-derived xenografts; hence, the importance of and PP2A activity for CML development and therapy.
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http://dx.doi.org/10.1158/0008-5472.BCD-19-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510943PMC
July 2020

On minor histocompatibility antigens, mixed chimerism, and transplantation tolerance.

Am J Transplant 2021 03 12;21(3):919-920. Epub 2020 Sep 12.

Division of Cancer Studies, King's College London University, London, UK.

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http://dx.doi.org/10.1111/ajt.16276DOI Listing
March 2021

Mesenchymal Stromal Cells for Graft Versus Host Disease: Mechanism-Based Biomarkers.

Front Immunol 2020 25;11:1338. Epub 2020 Jun 25.

School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom.

The immunosuppressive activity of mesenchymal stromal cells (MSCs) in graft versus host disease (GvHD) is well-documented, but their therapeutic benefit is rather unpredictable. Prospective randomized clinical trials remain the only means to address MSC clinical efficacy. However, the imperfect understanding of MSC biological mechanisms has undermined patients' stratification and the successful design of clinical studies. Furthermore, although MSC efficacy seems to be dependent on patient-associated factors, the role of patients' signature to predict and/or monitor clinical outcomes remains poorly elucidated. The analysis of GvHD patient serum has identified a set of molecules that are associated with high mortality. However, despite their importance in defining GvHD severity, their role in predicting or monitoring response to MSCs has not been confirmed. A new perspective on the use of MSCs for GvHD has been prompted by the recent findings that MSCs are actively induced to undergo apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. This discovery has not only reconciled the conundrum between MSC efficacy and their lack of engraftment, but also highlighted the determinant role of the patient in promoting and delivering MSC immunosuppression. In this review we will revisit the extensive use of MSCs for the treatment of GvHD and will elaborate on the need that future clinical trials must depend on mechanistic approaches that facilitate the development of robust and consistent assays to stratify patients and monitor clinical outcomes.
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http://dx.doi.org/10.3389/fimmu.2020.01338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330053PMC
April 2021

Acute myeloid leukemia shapes the bone marrow stromal niche .

Haematologica 2021 Mar 1;106(3):865-870. Epub 2021 Mar 1.

Centro Ricerca M. Tettamanti, Department of Pediatrics, University of Milano-Bicocca, Monza, Italy.

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http://dx.doi.org/10.3324/haematol.2020.247205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928008PMC
March 2021

The emergence of regenerative medicine in organ transplantation: 1st European Cell Therapy and Organ Regeneration Section meeting.

Transpl Int 2020 Aug 28;33(8):833-840. Epub 2020 Apr 28.

Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.

Regenerative medicine is emerging as a novel field in organ transplantation. In September 2019, the European Cell Therapy and Organ Regeneration Section (ECTORS) of the European Society for Organ Transplantation (ESOT) held its first meeting to discuss the state-of-the-art of regenerative medicine in organ transplantation. The present article highlights the key areas of interest and major advances in this multidisciplinary field in organ regeneration and discusses its implications for the future of organ transplantation.
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http://dx.doi.org/10.1111/tri.13608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497223PMC
August 2020

Phase I/II open-label trial of intravenous allogeneic mesenchymal stromal cell therapy in adults with recessive dystrophic epidermolysis bullosa.

J Am Acad Dermatol 2020 Aug 28;83(2):447-454. Epub 2019 Nov 28.

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK. Electronic address:

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary blistering disorder due to a lack of type VII collagen. At present, treatment is mainly supportive.

Objectives: To determine whether intravenous allogeneic bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs) are safe in RDEB adults and if the cells improve wound healing and quality of life.

Methods: We conducted a prospective, phase I/II, open-label study recruiting 10 RDEB adults to receive 2 intravenous infusions of BM-MSCs (on day 0 and day 14; each dose 2-4 × 10 cells/kg).

Results: BM-MSCs were well tolerated with no serious adverse events to 12 months. Regarding efficacy, there was a transient reduction in disease activity scores (8/10 subjects) and a significant reduction in itch. One individual showed a transient increase in type VII collagen.

Limitations: Open-label trial with no placebo.

Conclusions: MSC infusion is safe in RDEB adults and can have clinical benefits for at least 2 months.
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http://dx.doi.org/10.1016/j.jaad.2019.11.038DOI Listing
August 2020

Human Mesenchymal Stromal Cells Engineered to Express Collagen VII Can Restore Anchoring Fibrils in Recessive Dystrophic Epidermolysis Bullosa Skin Graft Chimeras.

J Invest Dermatol 2020 01 19;140(1):121-131.e6. Epub 2019 Jul 19.

Molecular and Cellular Immunology Unit, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.

Recessive dystrophic epidermolysis bullosa (RDEB) is a debilitating genodermatosis caused by loss-of-function mutations in COL7A1 encoding type VII collagen (C7), the main component of anchoring fibrils at the dermal-epidermal junction. With no curative treatments presently available, retrovirally transduced autologous epidermal grafts and intradermal lentivirally engineered fibroblast injections are being investigated. Alternative approaches aim to infuse allogeneic mesenchymal stromal cells (MSCs) to provide a more generalized treatment for RDEB. We investigated whether healthy human MSCs could be engineered to overexpress C7 and correct RDEB in a human:murine chimeric model. Initially, engineered MSCs incorporated ex vivo into RDEB grafts, their presence confirmed by fluorescence in situ hybridization, revealed recovery of function of the dermal-epidermal junction with no signs of blister formation. Importantly, the detection of anchoring fibrils by transmission electron microscopy corroborated structural recovery. Next, MSCs cotransduced to express C7 and luciferase were delivered intradermally into grafted RDEB skin, resulting in localized MSC persistence with deposition of de novo C7 at the site. Notably, C7 expression was sufficient to restore anchoring fibril density to normal levels. In contrast, intravenously injected engineered MSCs were undetectable within grafts and lacked anchoring fibril reconstitution. Our data suggest that although localized correction may be achievable using engineered MSCs, strategies for systemic administration require further modeling.
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http://dx.doi.org/10.1016/j.jid.2019.05.031DOI Listing
January 2020

Bone Marrow Transplantation 1957-2019.

Front Immunol 2019 5;10:1246. Epub 2019 Jun 5.

Division of Cancer Studies, King's College London, London, United Kingdom.

Clinical bone marrow transplantation started in 1957 at a time when remarkably little was known about hematopoietic stems cells, immune responses to transplants or the identity of transplant antigens. This review will delineate the substantial increase in knowledge about these three areas gained between then and 1992 when the Ceppellini School course on Bone Marrow Transplantation was held, along with the progress made in clinical application, as well as the stumbling blocks that remained to be overcome by further research to advance knowledge. It will outline the significant progress made between 1992 and the present year, 2019, and the remaining problems.
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http://dx.doi.org/10.3389/fimmu.2019.01246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560153PMC
October 2020

Acute myeloid leukaemia niche regulates response to L-asparaginase.

Br J Haematol 2019 08 1;186(3):420-430. Epub 2019 May 1.

M. Tettamanti Research Centre, Department of Paediatrics, University of Milano-Bicocca, Monza, Italy.

Eradicating the malignant stem cell is the ultimate challenge in the treatment of leukaemia. Leukaemic stem cells (LSC) hijack the normal haemopoietic niche, where they are mainly protected from cytotoxic drugs. The anti-leukaemic effect of L-asparaginase (ASNase) has been extensively investigated in acute lymphoblastic leukaemia, but only partially in acute myeloid leukaemia (AML). We explored the susceptibility of AML-LSC to ASNase as well as the role of the two major cell types that constitute the bone marrow (BM) microenvironment, i.e., mesenchymal stromal cells (MSC) and monocytes/macrophages. Whilst ASNase was effective on both CD34 CD38 and CD34 CD38 LSC fractions, MSC and monocytes/macrophages partially counteracted the effect of the drug. Indeed, the production of cathepsin B, a lysosomal cysteine protease, by BM monocytic cells and by AML cells classified as French-American-British M5 is related to the inactivation of ASNase. Our work demonstrates that, while MSC and monocytes/macrophages may provide a protective niche for AML cells, ASNase has a cytotoxic effect on AML blasts and, importantly, LSC subpopulations. Thus, these features should be considered in the design of future clinical studies aimed at testing ASNase efficacy in AML patients.
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http://dx.doi.org/10.1111/bjh.15920DOI Listing
August 2019

Is platelet gel safe enough for neutropenic patients?

Transfus Apher Sci 2019 04 19;58(2):190-191. Epub 2019 Mar 19.

Haematology Dept, Our Lady's Children's Hospital, Dublin, Ireland; University College Dublin, Ireland.

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http://dx.doi.org/10.1016/j.transci.2019.02.004DOI Listing
April 2019

Comparison of human isogeneic Wharton's jelly MSCs and iPSC-derived MSCs reveals differentiation-dependent metabolic responses to IFNG stimulation.

Cell Death Dis 2019 03 20;10(4):277. Epub 2019 Mar 20.

Department of Women and Children's Health, King's College London, Guy's Hospital, London, UK.

Variability among donors, non-standardized methods for isolation, and characterization contribute to mesenchymal stem/stromal cell (MSC) heterogeneity. Induced pluripotent stem cell (iPSCs)-derived MSCs would circumvent many of current issues and enable large-scale production of standardized cellular therapy. To explore differences between native MSCs (nMSCs) and iPSC-derived MSCs (iMSCs), we developed isogeneic lines from Wharton's jelly (WJ) from the umbilical cords of two donors (#12 and #13) under xeno-free conditions. Next, we reprogrammed them into iPSCs (iPSC12 and iPSC13) and subsequently differentiated them back into iMSCs (iMSC12 and iMSC13) using two different protocols, which we named ARG and TEX. We assessed their differentiation capability, transcriptome, immunomodulatory potential, and interferon-γ (IFNG)-induced changes in metabolome. Our data demonstrated that although both differentiation protocols yield iMSCs similar to their parental nMSCs, there are substantial differences. The ARG protocol resulted in iMSCs with a strong immunomodulatory potential and lower plasticity and proliferation rate, whereas the TEX protocol raised iMSCs with a higher proliferation rate, better differentiation potential, though weak immunomodulatory response. Our data suggest that, following a careful selection and screening of donors, nMSCs from umbilical's cord WJ can be easily reprogrammed into iPSCs, providing an unlimited source of material for differentiation into iMSCs. However, the differentiation protocol should be chosen depending on their clinical use.
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http://dx.doi.org/10.1038/s41419-019-1498-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426992PMC
March 2019

Apoptotic mesenchymal stromal cells induce prostaglandin E2 in monocytes: implications for the monitoring of mesenchymal stromal cell activity.

Haematologica 2019 10 7;104(10):e438-e441. Epub 2019 Mar 7.

School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom

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http://dx.doi.org/10.3324/haematol.2018.214767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886441PMC
October 2019

Challenges for mesenchymal stromal cell therapies.

Sci Transl Med 2019 02;11(480)

School of Cancer and Pharmacological Sciences, King's Health Partners Cancer Research UK Centre, King's College London, London SE1 9NH, UK.

Clinical trials of mesenchymal stromal cell therapies reveal a challenging heterogeneous landscape, including diverse therapeutic targets, patient categories, cell sources, and potential mechanisms of action.
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http://dx.doi.org/10.1126/scitranslmed.aat2189DOI Listing
February 2019

Mesenchymal stromal cells for acute graft-versus-host disease: response at 1 week predicts probability of survival.

Br J Haematol 2019 04 13;185(1):89-92. Epub 2019 Jan 13.

King's College London, London, UK.

Mesenchymal stromal cells (MSCs) have been successfully used for the treatment of steroid-resistant graft-versus-host-disease (GvHD). However, the lack of early predictors of clinical responses impacts on the time at which to add further treatment and consequently the design of informative clinical trials. Here, we present the UK experience of one of the largest cohorts of GvHD patients undergoing MSC infusions so far reported. We show that clinical responses assessed as early as 1 week after MSC infusion predict patients' overall survival. In our cohort, cell dose, patients' age and type of organ involvement are crucial factors associated with clinical responses.
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http://dx.doi.org/10.1111/bjh.15749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916615PMC
April 2019

Author Correction: Bi-directional cell-pericellular matrix interactions direct stem cell fate.

Nat Commun 2018 12 18;9(1):5419. Epub 2018 Dec 18.

Centre for Craniofacial and Regenerative Biology, King's College London, London, SE1 9RT, UK.

The original version of this Article contained an error in the author affiliations. The affiliation of Marjan Enayati with 'Ludwig Boltzmann Cluster for Cardiovascular Research at the Center for Biomedical Research, Medical University of Vienna, Austria' was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-07843-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299074PMC
December 2018

Author Correction: Bi-directional cell-pericellular matrix interactions direct stem cell fate.

Nat Commun 2018 11 14;9(1):4851. Epub 2018 Nov 14.

Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK.

In the original version of this Article the dataset identifier in the Data Availability statement was incorrect. The correct dataset identifier is PXD009500. This has been corrected in the HTML and PDF versions of this Article.
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http://dx.doi.org/10.1038/s41467-018-07398-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235857PMC
November 2018

Bi-directional cell-pericellular matrix interactions direct stem cell fate.

Nat Commun 2018 10 3;9(1):4049. Epub 2018 Oct 3.

Centre for Craniofacial and Regenerative Biology, King's College London, London, SE1 9RT, UK.

Modifiable hydrogels have revealed tremendous insight into how physical characteristics of cells' 3D environment drive stem cell lineage specification. However, in native tissues, cells do not passively receive signals from their niche. Instead they actively probe and modify their pericellular space to suit their needs, yet the dynamics of cells' reciprocal interactions with their pericellular environment when encapsulated within hydrogels remains relatively unexplored. Here, we show that human bone marrow stromal cells (hMSC) encapsulated within hyaluronic acid-based hydrogels modify their surroundings by synthesizing, secreting and arranging proteins pericellularly or by degrading the hydrogel. hMSC's interactions with this local environment have a role in regulating hMSC fate, with a secreted proteinaceous pericellular matrix associated with adipogenesis, and degradation with osteogenesis. Our observations suggest that hMSC participate in a bi-directional interplay between the properties of their 3D milieu and their own secreted pericellular matrix, and that this combination of interactions drives fate.
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http://dx.doi.org/10.1038/s41467-018-06183-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170409PMC
October 2018

Multiparametric Analysis of Circulating Exosomes and Other Small Extracellular Vesicles by Advanced Imaging Flow Cytometry.

Front Immunol 2018 6;9:1583. Epub 2018 Jul 6.

MRC Centre for Transplantation, Institute of Liver Studies, King's College London, London, United Kingdom.

Extracellular vesicles (EVs) are responsible for a multitude of physiological functions, including immunomodulation. A heterogenous mixture of small EV (sEV) subsets, including putative exosomes, is derived when commonly used "exosome" isolation techniques are employed. Subset diversity relates in part to their different intracellular origins, and can be associated with distinct functional properties. Recent progress in the EV field has enabled the categorization of such subsets based on their surface composition. For the first time, we combine such emerging subset-specific markers with advanced imaging flow cytometry (iFCM) to perform high-throughput, multiparametric, vesicle-by-vesicle characterization, and functional assessment of specific small EV subsets, and exosomes in particular. The approach allows researchers to address three important applications. First, it is known that different isolation techniques result in the divergent recovery of particular vesicle subsets. Taking three commonly used "exosome" isolation techniques as test cases (ultracentrifugation, size-exclusion chromatography, and polymer-based precipitation), the capacity for convenient and accurate isolate compositional analysis by iFCM is demonstrated. The approach was able to corroborate and to quantify the known skewing of subtype recovery among different isolation approaches. Second, exosomes are a particularly widely studied EV subset. Applying exosome-specific markers to samples collected from an optimal clinical transplantation model, we verify the capacity for iFCM to detect exosomes in circulation, to establish their tissue of origin, and to provide insights as to their functional immunological potential. Finally, we describe a technique for establishing whether the transfer of a molecule of interest to a target cell is exosomally mediated. In so doing, we highlight the approach's utility in assessing the functional of circulating exosomes and in identifying their targets. In conclusion, we set out a new methodological approach by which small extracellular vesicle subsets, exosomes in particular, can be conveniently and comprehensively investigated, thereby offering novel phenotypic and functional insights.
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http://dx.doi.org/10.3389/fimmu.2018.01583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043651PMC
July 2018

Manufacturing Mesenchymal Stromal Cells for the Treatment of Graft-versus-Host Disease: A Survey among Centers Affiliated with the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2018 11 20;24(11):2365-2370. Epub 2018 Jul 20.

School of Cancer & Pharmaceutical Sciences, King's College London, London, United Kingdom. Electronic address:

The immunosuppressive properties of mesenchymal stromal cells (MSC) have been successfully tested to control clinical severe graft-versus host disease and improve survival. However, clinical studies have not yet provided conclusive evidence of their efficacy largely because of lack of patients' stratification criteria. The heterogeneity of MSC preparations is also a major contributing factor, as manufacturing of therapeutic MSC is performed according to different protocols among different centers. Understanding the variability of the manufacturing protocol would allow a better comparison of the results obtained in the clinical setting among different centers. In order to acquire information on MSC manufacturing we sent a questionnaire to the European Society for Blood and Marrow Transplantation centers registered as producing MSC. Data from 17 centers were obtained and analyzed by means of a 2-phase questionnaire specifically focused on product manufacturing. Gathered information included MSC tissue sources, MSC donor matching, medium additives for ex vivo expansion, and data on MSC product specification for clinical release. The majority of centers manufactured MSC from bone marrow (88%), whilst only 2 centers produced MSC from umbilical cord blood or cord tissue. One of the major changes in the manufacturing process has been the replacement of fetal bovine serum with human platelet lysate as medium supplement. 59% of centers used only third-party MSC, whilst only 1 center manufactured exclusively autologous MSC. The large majority of these facilities (71%) administered MSC exclusively from frozen batches. Aside from variations in the culture method, we found large heterogeneity also regarding product specification, particularly in the markers used for phenotypical characterization and their threshold of expression, use of potency assays to test MSC functionality, and karyotyping. The initial data collected from this survey highlight the variability in MSC manufacturing as clinical products and the need for harmonization. Until more informative potency assays become available, a more homogeneous approach to cell production may at least reduce variability in clinical trials and improve interpretation of results.
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http://dx.doi.org/10.1016/j.bbmt.2018.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299357PMC
November 2018

Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies.

Sci Transl Med 2018 04;10(436)

Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, University Vita-Salute San Raffaele and Ospedale San Raffaele Scientific Institute, 20132 Milan, Italy.

Over the last 60 years, more than a million patients received hematopoietic cell transplantation. Having incorporated multiple changes in clinical practices, it remains a complex procedure facing a dual challenge: cure of the underlying disease and prevention of relapse while controlling potentially severe complications. Improved understanding of underlying biological processes resulted in the design of innovative therapies engineered from defined cell populations and testing of these therapies as addition or substitution at virtually every step of the procedure. This review provides an overview of these developments, many of them now applied outside the historical field of hematopoietic cell transplantation.
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http://dx.doi.org/10.1126/scitranslmed.aap9630DOI Listing
April 2018

Mesenchymal-myeloid interaction in the regulation of immunity.

Semin Immunol 2018 02 1;35:59-68. Epub 2018 Feb 1.

School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom. Electronic address:

Several studies have demonstrated how different cell types of mesenchymal and myeloid origin can independently exhibit immunoregulatory activities. In response to inflammatory cues, they transcribe a molecular repertoire that restores the tissue microenvironment to what it was before the injury. There is accumulating evidence that stromal and myeloid-derived cells do not act independently but that the establishment of a cross-talk between them is a fundamental requirement. Stromal cells, prompted by inflammatory molecules, orchestrate and initiate myeloid cell recruitment and their functional reprogramming. Once instructed, myeloid cells effect the anti-inflammatory activity or, if alternatively required, enhance immune responses. The cross-talk plays a fundamental role in tissue homeostasis, not only to regulate inflammation, but also to promote tissue regeneration and cancer progression.
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http://dx.doi.org/10.1016/j.smim.2018.01.002DOI Listing
February 2018

Repurposing Tin Mesoporphyrin as an Immune Checkpoint Inhibitor Shows Therapeutic Efficacy in Preclinical Models of Cancer.

Clin Cancer Res 2018 04 16;24(7):1617-1628. Epub 2018 Jan 16.

School of Cancer and Pharmaceutical Sciences, King's College London, Faculty of Life Sciences and Medicine, Guy's Hospital, London, United Kingdom.

Unprecedented clinical outcomes have been achieved in a variety of cancers by targeting immune checkpoint molecules. This preclinical study investigates heme oxygenase-1 (HO-1), an immunosuppressive enzyme that is expressed in a wide variety of cancers, as a potential immune checkpoint target in the context of a chemotherapy-elicited antitumor immune response. We evaluate repurposing tin mesoporphyrin (SnMP), which has demonstrated safety and efficacy targeting hepatic HO in the clinic for the treatment of hyperbilirubinemia, as an immune checkpoint blockade therapy for the treatment of cancer. SnMP and genetic inactivation of myeloid HO-1 were evaluated alongside 5-fluorouracil in an aggressive spontaneous murine model of breast cancer (). Single-cell RNA sequencing analysis, tumor microarray, and clinical survival data from breast cancer patients were used to support the clinical relevance of our observations. We demonstrate that SnMP inhibits immune suppression of chemotherapy-elicited CD8 T cells by targeting myeloid HO-1 activity in the tumor microenvironment. Microarray and survival data from breast cancer patients reveal that HO-1 is a poor prognostic factor in patients receiving chemotherapy. Single-cell RNA-sequencing analysis suggests that the myeloid lineage is a significant source of HO-1 expression, and is co-expressed with the immune checkpoints PD-L1/2 in human breast tumors. we therapeutically compare the efficacy of targeting these two pathways alongside immune-stimulating chemotherapy, and demonstrate that the efficacy of SnMP compares favorably with PD-1 blockade in preclinical models. SnMP could represent a novel immune checkpoint therapy, which may improve the immunological response to chemotherapy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889101PMC
April 2018

Preclinical imaging methods for assessing the safety and efficacy of regenerative medicine therapies.

NPJ Regen Med 2017 19;2:28. Epub 2017 Oct 19.

Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.

Regenerative medicine therapies hold enormous potential for a variety of currently incurable conditions with high unmet clinical need. Most progress in this field to date has been achieved with cell-based regenerative medicine therapies, with over a thousand clinical trials performed up to 2015. However, lack of adequate safety and efficacy data is currently limiting wider uptake of these therapies. To facilitate clinical translation, non-invasive in vivo imaging technologies that enable careful evaluation and characterisation of the administered cells and their effects on host tissues are critically required to evaluate their safety and efficacy in relevant preclinical models. This article reviews the most common imaging technologies available and how they can be applied to regenerative medicine research. We cover details of how each technology works, which cell labels are most appropriate for different applications, and the value of multi-modal imaging approaches to gain a comprehensive understanding of the responses to cell therapy in vivo.
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http://dx.doi.org/10.1038/s41536-017-0029-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677988PMC
October 2017

Roadmap to clinical translation: insights from a UK regenerative medicine platform workshop on mesenchymal stromal cells.

Regen Med 2017 Dec 15;12(8):895-897. Epub 2017 Dec 15.

Department of Haemato-Oncology, Rayne Institute, 123 Coldharbour Lane, London, SE5 9NU, UK.

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http://dx.doi.org/10.2217/rme-2017-0097DOI Listing
December 2017

Effects of maternal obesity on Wharton's Jelly mesenchymal stromal cells.

Sci Rep 2017 12 14;7(1):17595. Epub 2017 Dec 14.

Stem Cell Laboratory, Assisted Conception Unit, School of Life Course Sciences, Department of Women and Children's Health, Faculty of Life Sciences & Medicine, King's College London, London, UK.

We investigated whether maternal metabolic environment affects mesenchymal stromal/stem cells (MSCs) from umbilical cord's Wharton's Jelly (WJ) on a molecular level, and potentially render them unsuitable for clinical use in multiple recipients. In this pilot study on umbilical cords post partum from healthy non-obese (BMI = 19-25; n = 7) and obese (BMI ≥ 30; n = 7) donors undergoing elective Cesarean section, we found that WJ MSC from obese donors showed slower population doubling and a stronger immunosuppressive activity. Genome-wide DNA methylation of triple positive (CD73CD90CD105) WJ MSCs found 67 genes with at least one CpG site where the methylation difference was ≥0.2 in four or more obese donors. Only one gene, PNPLA7, demonstrated significant difference on methylome, transcriptome and protein level. Although the number of analysed donors is limited, our data suggest that the altered metabolic environment related to excessive body weight might bear consequences on the WJ MSCs.
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http://dx.doi.org/10.1038/s41598-017-18034-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730612PMC
December 2017

Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation.

Sci Transl Med 2017 Nov;9(416)

Regenerative Medicine, Division of Cancer Studies and Cancer Research UK King's Health Partners, King's College London, London SE5 9NU, UK.

The immunosuppressive activity of mesenchymal stromal cells (MSCs) is well documented. However, the therapeutic benefit is completely unpredictable, thus raising concerns about MSC efficacy. One of the affecting factors is the unresolved conundrum that, despite being immunosuppressive, MSCs are undetectable after administration. Therefore, understanding the fate of infused MSCs could help predict clinical responses. Using a murine model of graft-versus-host disease (GvHD), we demonstrate that MSCs are actively induced to undergo perforin-dependent apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. When examining patients with GvHD who received MSCs, we found a striking parallel, whereby only those with high cytotoxic activity against MSCs responded to MSC infusion, whereas those with low activity did not. The need for recipient cytotoxic cell activity could be replaced by the infusion of apoptotic MSCs generated ex vivo. After infusion, recipient phagocytes engulf apoptotic MSCs and produce indoleamine 2,3-dioxygenase, which is ultimately necessary for effecting immunosuppression. Therefore, we propose the innovative concept that patients should be stratified for MSC treatment according to their ability to kill MSCs or that all patients could be treated with ex vivo apoptotic MSCs.
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http://dx.doi.org/10.1126/scitranslmed.aam7828DOI Listing
November 2017

Advances in mesenchymal stromal cell therapy in the management of Crohn's disease.

Expert Rev Gastroenterol Hepatol 2018 Feb 2;12(2):141-153. Epub 2017 Nov 2.

a Department of Gastroenterology , Guy's and St Thomas' Hospital , London , UK.

Introduction: The aim of therapy in Crohn's disease (CD) is induction and maintenance of remission, promotion of mucosal healing and restoration of quality of life. Even the best treatment regimes, including combinations of biologics and immunomodulators lack durable efficacy and have well documented side effects. Accordingly, there is an unmet need for novel therapies. Mesenchymal stromal cells (MSCs) are a subset of non-hematopoietic stem cells that home to sites of inflammation where they exert potent immunomodulatory effects and contribute to tissue repair. Their utility is being explored in several inflammatory and immune mediated disorders including CD, where they have demonstrated favourable safety, feasibility and efficacy profiles. Areas covered: This review highlights current knowledge on MSC therapy and critically evaluates their safety, efficacy and potential mechanisms of action in CD. Expert commentary: Building on positive early phase clinical trials and a recent phase 3 trial in perianal CD, there is considerable optimism for the possibility of MSCs changing the treatment landscape in complicated CD. Although important questions remain unanswered, including the safety and durability of MSC therapy, optimal adjunctive therapies and their sourcing and manufacturing, it is anticipated that MSCs are likely to enter mainstream treatment algorithms in the near future.
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http://dx.doi.org/10.1080/17474124.2018.1393332DOI Listing
February 2018