Distinct Roles of Bcl-2 and Bcl-Xl in the Apoptosis of Human Bone Marrow Mesenchymal Stem Cells during Differentiation

Background: Adult mesenchymal stem cells (MSCs) can be maintained over extended periods of time before activation and differentiation. Little is known about the programs that sustain the survival of these cells. Principal Findings: Undifferentiated adult human MSCs (hMSCs) did not undergo apoptosis in response to different cell death inducers. Conversely, the same inducers can readily induce apoptosis when hMSCs are engaged in the early stages of differentiation. The survival of undifferentiated cells is linked to the expression of Bcl-Xl and Bcl-2 in completely opposite ways. Bcl-Xl is expressed at similar levels in undifferentiated and differentiated hMSCs while Bcl-2 is expressed only in differentiated cells. In undifferentiated hMSCs, the down-regulation of Bcl-Xl is associated with an increased sensitivity to apoptosis while the ectopic expression of Bcl-2 induced apoptosis. This apoptosis is linked to the presence of cytoplasmic Nur 77 in undifferentiated hMSCs. Significance: In hMSCs, the expression of Bcl-2 depends on cellular differentiation and can be either pro- or anti-apoptotic. Bcl-Xl, on the other hand, exhibits an anti-apoptotic activity under all conditions

Concise Review: Stem/progenitor cell proteoglycans decorated with 7-D-4, 4-C-3, and 3-B-3(-) chondroitin sulfate motifs are morphogenetic markers of tissue development

This study reviewed the occurrence of chondroitin sulfate (CS) motifs 4‐C‐3, 7‐D‐4, and 3‐B‐3(‐), which are expressed by progenitor cells in tissues undergoing morphogenesis. These motifs have a transient early expression pattern during tissue development and also appear in mature tissues during pathological remodeling and attempted repair processes by activated adult stem cells. The CS motifs are information and recognition modules, which may regulate cellular behavior and delineate stem cell niches in developmental tissues. One of the difficulties in determining the precise role of stem cells in tissue development and repair processes is their short engraftment period and the lack of specific markers, which differentiate the activated stem cell lineages from the resident cells. The CS sulfation motifs 7‐D‐4, 4‐C‐3, and 3‐B‐3 (‐) decorate cell surface proteoglycans on activated stem/progenitor cells and appear to identify these cells in transitional areas of tissue development and in tissue repair and may be applicable to determining a more precise role for stem cells in tissue morphogenesis. Stem Cells 201

Low temperature exposure induces browning of bone marrow stem cell derived adipocytes in vitro

Brown and beige adipocytes are characterised as expressing the unique mitochondrial uncoupling protein (UCP)1 for which the primary stimulus in vivo is cold exposure. The extent to which cold-induced UCP1 activation can also be achieved in vitro, and therefore perform a comparable cellular function, is unknown. We report an in vitro model to induce adipocyte browning using bone marrow (BM) derived mesenchymal stem cells (MSC), which relies on differentiation at 32°C instead of 37°C. The low temperature promoted browning in adipogenic cultures, with increased adipocyte differentiation and upregulation of adipogenic and thermogenic factors, especially UCP1. Cells exhibited enhanced uncoupled respiration and metabolic adaptation. Cold-exposed differentiated cells showed a marked translocation of leptin to adipocyte nuclei, suggesting a previously unknown role for leptin in the browning process. These results indicate that BM-MSC can be driven to forming beige-like adipocytes in vitro by exposure to a reduced temperature. This in vitro model will provide a powerful tool to elucidate the precise role of leptin and related hormones in hitherto functions in the browning process

Oncology and complications.

This collection of cases describes some unusual urological tumors and complications related to urological tumors and their treatment. Case 1: A case of uretero-arterial fistula in a patient with long-term ureteral stenting for ureteral oncological stricture and a second case associated to retroperitoneal fibrosis were described. Abdominal CT, pyelography, cystoscopy were useful to show the origin of the bleeding. Angiography is useful for confirming the diagnosis and for subsequent positioning of an endovascular prosthesis which represents a safe approach with reduced post-procedural complications. Case 2: A case of patient who suffered from interstitial pneumonitis during a cycle of intravesical BCG instillations for urothelial cancer. The patient was hospitalized for more than two weeks in a COVID ward for a suspected of COVID-19 pneumonia, but he did not show any evidence of SARS-CoV-2 infection during his hospital stay. Case 3: A case of a young man with a functional urinary bladder paraganglioma who was successfully managed with complete removal of the tumor, leaving the urinary bladder intact. Case 4: A case of a 61 year old male suffering from muscle invasive bladder cancer who was admitted for a radical cystectomy and on the eighth postoperative day developed microangiopathic hemolytic anemia and thrombocytopenia, which clinically defines thrombotic microangiopathy

Pericyte-Like Progenitors Show High Immaturity and Engraftment Potential as Compared with Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) and pericyte progenitors (PPs) are both perivascular cells with similar multipotential properties regardless of tissue of origin. We compared the phenotype and function of the 2 cell types derived from the same bone-marrow samples but expanded in their respective media – pericyte conditions (endothelial cell growth medium 2 [EGM-2]) for PPs and standard medium (mesenchymal stem cell medium [MSM]) for MSCs. After 3 weeks of culture, whatever the expansion medium, all cells showed similar characteristics (MSC markers and adipo-osteo-chondroblastic differentiation potential), although neuronal potential was greater in EGM-2– than MSM-cultured cells. As compared with MSM-cultured MSCs, EGM-2–cultured PPs showed higher expression of the pericyte-specific antigen 3G5 than a-smooth muscle actin. In addition, EGM-2–cultured PPs showed an immature phenotype, with upregulation of stemness OCT4 and SOX2 proteins and downregulation of markers of osteoblastic, chondroblastic, adipocytic and vascular smooth muscle lineages. Despite having less effective in vitro immunosuppression capacities than standard MSCs, EGM-2–cultured PPs had higher engraftment potentials when combined with biomaterials heterotopically-transplanted in Nude mice. Furthermore, these engrafted cells generated more collagen matrix and were preferentially perivascular or lined trabeculae as compared with MSM-cultured MSCs. In conclusion, EGM-2–cultured PPs are highly immature cells with increased plasticity and engraftment potential

Διαταραχές της ερυθροποίησης στους πάσχοντες από χρονία ιδιοπαθή ουδετεροπενία

Προκειμένου να διερευνηθούν οι παθογενετικοί μηχανισμοί της αναιμίας στη χρονία ιδιοπαθή ουδετεροπενία (CIN) μελετήθηκαν οι εφεδρείες και τα λειτουργικά χαρακτηριστικά των κυττάρων της ερυθράς σειράς στον μυελό των οστών (BM) σε 10 επιλεγμένους ασθενείς με CIN και αναιμία χρονίας νόσου (ΑCD), 27 μη-αναιμικούς ασθενείς με CIN και 30 υγιείς μάρτυρες, χρησιμοποιώντας κυτταρομετρία ροής και κλωνογονικές δοκιμασίες. Bρέθηκε ότι οι ασθενείς με CIN στο σύνολό τους, καθώς και εκείνοι με CIN και ACD είχαν μικρότερο αριθμό CD34+/CD71+ προγονικών κυττάρων της ερυθράς σειράς, αλλά και ώριμων CD36-/GlycoA+ερυθροκυτταρικών προβαθμίδων, σε σύγκριση με τους υγιείς μάρτυρες. Ο αριθμός των CD34+/CD71+ κυττάρων ήταν μικρότερος και στους μη αναιμικούς ασθενείς με CIN, σε σχέση με τους υγιείς μάρτυρες, ενώ δεν υπήρχε διαφορά στις CD36-/GlycoA+ ερυθροκυτταρικές προβαθμίδες. Τόσο οι ασθενείς με CIN στο σύνολό τους όσο και οι μη αναιμικοί με CIN, αλλά και εκείνοι με CIN και ACD είχαν αυξημένη απόπτωση στα CD34+/CD71+ κύτταρα, καθώς και στις CD36+/GlycoA+ ενδιάμεσες ερυθροκυτταρικές προβαθμίδες. Ο αριθμός των ερυθροκυτταρικών αποικιών (BFU-e) που λαμβάνονταν από μυελικά μονοπύρηνα (BMMCs) και καθαρά CD34+ κύτταρα, αντιστοιχούντα στις προγονικές αιμοποιητικές προβαθμίδες ήταν μειωμένος στους σύνολο των πασχόντων με CIN, καθώς και στους μη αναιμικούς με CIN, αλλά και σ' εκείνους με CIN και ACD, σε σύγκριση με τους υγιείς μάρτυρες. Παρατηρήθηκε επίσης ότι η τοπική -στο μυελό- παραγωγή παράγοντα νέκρωσης των όγκων-άλφα (TNFα) και ιντερφερόνης-γάμμα (IFNγ) ήταν υψηλότερη στους ασθενείς με CIN καιACD, σε σύγκριση με τους υγιείς μάρτυρες. Παρατηρήθηκε επίσης ότι η τοπική -στο μυελό- παραγωγή παράγοντα νέκρωσης των όγκων-άλφα (TNFα) και ιντερφερόνης-γάμμα (IFNγ) ήταν υψηλότερη στους ασθενείς με CIN και ΑCD, καθώς και στους μη αναιμικούς με CΙΝ, σε σύγκριση με τους μάρτυρες. Ακόμα, ο αριθμός των BFU-e στους ασθενείς με CIN αυξήθηκε σημαντικά μετά από in vitro επώαση με αντισώματα έναντι του TNFα και της IFNγ. Επιπρόσθετα, - 23- διαπιστώθηκε ότι η παραγωγή ερυθροποιητίνης (Epo) στους πάσχοντες ήταν η προβλεπόμενη για τη βαρύτητα της αναιμίας, αλλά η έκφραση του υποδοχέα αυτής (EpoR) ήταν σημαντικά μειωμένη στα GlycoA+ κύτταρα των ασθενών με CIN και ΑCD. Τέλος, παρατηρήθηκε ότι η επώαση φυσιολογικών GlycoA+ κυττάρων με ανασυνδυασμένο ΤNFα και/ή IFNγ είχε ως αποτέλεσμα την καταστολή της έκφρασηςτων EpoR. Συμπερασματικά η μείωση της ερυθροποίησης στους πάσχοντες από CIN οφείλεται, σε μεγάλο βαθμό, στην αυξημένη τοπική παραγωγή TNFα και IFNγ στο μυελό, που επάγουν την απόπτωση, αναστέλλουν την κυτταρική ανάπτυξη και καταστέλλουν την έκφραση του EpoR στις ερυθροκυτταρικές προβαθμίδες