Sandra Jacobs

Differentiation Potential of Human Postnatal Mesenchymal Stem Cells, Mesoangioblasts, and Multipotent Adult Progenitor Cells Reflected in Their Transcriptome and Partially Influenced by the Culture Conditions†‡§

Several adherent postnatal stem cells have been described with different phenotypic and functional properties. As many of these cells are being considered for clinical therapies, it is of great importance that the identity and potency of these products is validated. We compared the phenotype and functional characteristics of human mesenchymal stem cells (hMSCs), human mesoangioblasts (hMab), and human multipotent adult progenitor cells (hMAPCs) using uniform standardized methods. Human MAPCs could be expanded significantly longer in culture. Differences in cell surface marker expression were found among the three cell populations with CD140b being a distinctive marker among the three cell types. Differentiation capacity towards adipocytes, osteoblasts, chondrocytes, and smooth muscle cells in vitro, using established protocols, was similar among the three cell types. However, only hMab differentiated to skeletal myocytes, while only hMAPCs differentiated to endothelium in vitro and in vivo. A comparative transcriptome analysis confirmed that the three cell populations are distinct and revealed gene signatures that correlated with their specific functional properties. Furthermore, we assessed whether the phenotypic, functional, and transcriptome features were mediated by the culture conditions. Human MSCs and hMab cultured under MAPC conditions became capable of generating endothelial‐like cells, whereas hMab lost some of their ability to generate myotubes. By contrast, hMAPCs cultured under MSC conditions lost their endothelial differentiation capacity, whereas this was retained when cultured under Mab conditions, however, myogenic capacity was not gained under Mab conditions. These studies demonstrate that hMSCs, hMab, and hMAPCs have different properties that are partially mediated by the culture conditions. STEM CELLS 2011;29:871–882

Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells

Somatic, also termed adult, stem cells are highly attractive biomedical cell candidates because of their extensive replication potential and functional multilineage differentiation capacity. They can be used for drug and toxicity screenings in preclinical studies, as in vitro model to study differentiation or for regenerative medicine to aid in the repair of tissues or replace tissues that are lost upon disease, injury or ageing. Multipotent adult progenitor cells (MAPCs) and mesenchymal stem cells (MSCs) are two types of adult stem cells derived from bone marrow that are currently being used clinically for tissue regeneration and for their immunomodulatory and trophic effects. This review will give an overview of the phenotypic and functional differences between human MAPCs and MSCs, with a strong emphasis on their immunological characteristics. Finally, we will discuss the clinical studies in which MSCs and MAPCs are already used.

Human multipotent adult progenitor cells are nonimmunogenic and exert potent immunomodulatory effects on alloreactive T-cell responses.

Multipotent adult progenitor cells (MAPCs) are bone marrow-derived nonhematopoietic stem cells with a broad differentiation potential and extensive expansion capacity. A comparative study between human mesenchymal stem cells (hMSCs) and human MAPCs (hMAPCs) has shown that hMAPCs have clearly distinct phenotypical and functional characteristics from hMSCs. In particular, hMAPCs express lower levels of MHC class I than hMSCs and cannot only differentiate into typical mesenchymal cell types but can also differentiate in vitro and in vivo into functional endothelial cells. The use of hMSCs as cellular immunomodulatory stem cell products gained much interest since their immunomodulatory capacities in vitro became evident over the last decade. Currently, the clinical grade stem cell product of hMAPCs is already used in clinical trials to prevent graft-versus-host disease (GVHD), as well as for the treatment of acute myocardial infarct, ischemic stroke, and Crohns disease. Therefore, we studied the immune phenotype, immunogenicity, and immunosuppressive effect of hMAPCs in vitro. We demonstrated that hMAPCs are nonimmunogenic for T-cell proliferation and cytokine production. In addition, hMAPCs exert strong immunosuppressive effects on T-cell alloreactivity and on T-cell proliferation induced by mitogens and recall antigens. This immunomodulatory effect was not MHC restricted, which makes off-the-shelf use promising. The immunosuppressive effect of hMAPCs is partially mediated via soluble factors and dependent on indoleamine 2,3-dioxygenase (IDO) activity. At last, we isolated hMAPCs, the clinical grade stem cell product of hMAPCs, named MultiStem, and hMSCs from one single donor and observed that both the immunogenicity and the immunosuppressive capacities of all three stem cell products are comparable in vitro. In conclusion, hMAPCs have potent immunomodulatory properties in vitro and can serve as a valuable cell source for the clinical use of immunomodulatory cellular stem cell product.

Diverse Cutaneous Presentations of Langerhans Cell Histiocytosis in Children: A Retrospective Cohort Study

Langerhans cell histiocytosis (LCH) is a rare disease, frequently affecting young children.

Mutual Interaction Between Human Multipotent Adult Progenitor Cells and NK Cells

Human multipotent adult progenitor cells (hMAPCs) are isolated from bone marrow with a more extensive expansion capacity compared to human mesenchymal stem cells (hMSCs) and with the ability to differentiate into endothelium. Like hMSCs, hMAPCs inhibit T-cell proliferation induced by alloantigens. In this study, we tested the interaction between hMAPCs and natural killer (NK) cells. We assessed the susceptibility of hMAPCs to NK cell-mediated lysis and the immunomodulation of hMAPCs on NK cell function during IL-2-driven stimulation and the cytolytic effector phase. Human MAPCs express the ligands PVR and ULBP-2/5/6, which are recognized by activating NK cell receptors. However, they also express MHC class I molecules, which induce inhibitory signals in NK cells. Freshly isolated NK cells at different effector:target ratios did not kill hMAPCs as assessed by an MTT and 51Cr-release assay, while hMAPCs impaired the cytotoxic activity of resting NK cells against the NK-sensitive K562 leukemia cell line. By contrast, IL-2-stimulated NK cells were capable of killing hMAPCs, and preactivated NK cells were not influenced during their cytotoxic effector function against K562 cells by hMAPCs. When added during the 6-day preactivation phase with IL-2, hMAPCs dose-dependently reduced NK cell proliferation in an IDO-dependent manner, but they did not influence the induction of cytotoxic capacity by IL-2. This study indicates that human MAPCs mutually interact with NK cells.

Primary myxoid mesenchymal tumor with intracranial location: report of a case with a EWSR1-ATF1 fusion

About a third of soft tissue tumors are recognized by gene fusions. Some of these fusions are not histotype specific and occur in entities with totally different clinicopathological features. A good example is the fusion between EWSR1 and genes of the CREB transcription factor gene family (CREB1 or ATF1). This article is protected by copyright. All rights reserved.

Altering the Biodegradation of Mesoporous Silica Nanoparticles by Means of Experimental Parameters and Surface Functionalization

Mesoporous silica nanoparticles (MSNPs) are gaining a large interest in the field of medical and biomedical applications due to their biodegradability and high loading capacity as a carrier. In this work, a simple synthesis and functionalization procedure is reported, which allows tuning the nanoparticle properties, functionalization, and biodegradability. Variations in the synthesis procedure are introduced, including temperature, concentration of catalyst, and surface functionalization. These samples are characterized and afterwards degraded in phosphate buffered saline (PBS) to determine their degradation kinetics. The amount of degraded material is colorimetrically determined, using an optimized protocol based on molybdenum blue chemistry. It is shown that the degradability of the nanoparticles increased with decreasing synthesis temperatures, lower amounts of catalyst, and higher concentrations of nanoparticles. Surface functionalization alters the degradation kinetics as well, rendering amino-functionalized nanoparticles the fastest degradation behavior, followed by carboxylated and nonfunctionalized nanoparticles. From these results, it can be concluded that the degradation rate of MSNPs can be varied from a few hours to several days by small changes in the synthesis procedure. Moreover, the degradation behavior is strongly dependent on the nanoparticle growth rate.

Ophthalmological examination in neurofibromatosis type 1: a long-term retrospective analysis

tive vitreoretinopathy (Mulder et al. 2017). Here, we measured aqueous flare in patients with wAMD, diabetic macular oedema (DME), cystoid macular oedema (CME) due to retinal vein occlusion (RVO) and CME related to other retinal disease, including eyes with, for example pseudophakic, myopic and postvitrectomy CME and chronic serous chorioretinopathy. The patients were receiving treatment with antivascular endothelial growth factor injections (anti-VEGF) and analysed according to whether the injections were continued or whether no injections were needed. Aqueous flare values were measured using a laser flaremeter (FM-600,Kowa Company, Ltd., Nagoya, Japan) and a mean of five reliable measurements was used in the analysis. Aqueous flare was measured in the beginning of each visit before the injection or the decision to follow without injection. No dilating drops were installed before themeasurements. All the measurements were performed by an experienced research technician blinded from the treating physician. The study was conducted by monitoring the clinical practice. To patients with wAMD, anti-VEGF treatment (aflibercept or bevacizumab) was given using the treat-and-extend (TER) protocol (n = 189). The need for retreatment was evaluated before each injection, and the treatment interval was gradually extended up to a maximum of 12 weeks. After successfully reaching the 12-week interval, patients with inactive disease (n = 13)were observedwithout treatment. In patients with DME (n = 50),RVO(n = 28)andother retinal disease (n = 14), a fixed-PRN protocol was used. Patients were given three monthly anti-VEGF injections and then evaluated 6 weeks after the last injection regardless of the anti-VEGF agent. In the absence of macular oedema, followupwasorganizedat theoutpatient clinic. Aqueous flare was higher among patient groups during anti-VEGF treatment compared to visits when no treatment was necessary (Table 1). In wAMD patients, flare values were 22.7 35.5 photon units (pu)/ms (mean SD) during treatment versus 10.9 5.2 pu/mswhenno injectionwas given (p < 0.001). In DME patients, the values were 19.7 16.6 pu/ms versus 7.1 2.9 pu/ms (p = 0.009), and in patients with other retinal disease 28.7 31.8 pu/ms versus 6.2 2.2 pu/ ms (p = 0.021) respectively. Our data suggest that aqueous flare reflects retinal disease activity by decreasing during treatment-free periods. Further studies are still warranted to investigate whether aqueousflare canbeused tohelpestimate optimal follow-up interval and risk of reactivation in patients with anti-VEGF injections for retinal diseases.