Repopulation
Dotaz
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Repopulace decelularizované tkáně buňkami je velmi nadějným směrem, kterým by se mohl řešit nedostatek tkání a orgánů pro transplantace, přičemž jaterní tkáňové inženýrství není výjimkou. Decelularizovaný jaterní skelet slouží jako ideální 3D prostředí pro recelularizaci, neboť je v něm zachována tkáňově specifická mikroarchitektura proteinů extracelulární matrix (ECM) s poziční informací jak pro osídlení novými buňkami, tak pro jejich migraci, růst a diferenciaci. Při použití autologních buněk by navíc nově konstruovaný štěp měl postrádat imunogenicitu v hostitelském organismu, bylo by tedy možné se kompletně vyhnout imunosupresi, která je v současnosti nutnou součástí terapie po transplantaci. Tento přehled uvádí příklady dosud provedených decelularizačních a repopulačních experimentů v játrech, přičemž upozorňuje na pokroky a poukazuje na výzvy, které je třeba řešit.
Repopulation of decellularized tissue with cells is a very promising approach in tissue engineering, with liver tissue engineering not being an exception. Decellularized liver scaffolds can serve as an excellent 3D environment for recellularization as it maintain tissue-specific microarchitecture of ECM proteins with important spatial cues for cell adhesion, migration, growth and differentiation. Moreover, by using autologous cells the newly constructed graft should lack immunogenicity in the host organism and thus eliminate the need for immunosuppressive therapy in the post-transplant period. This review provides an overview of liver decellularization and repopulation experiments done so far while highlighting the advances as well as pin-pointing the challenges that remain to be solved.
- Klíčová slova
- decelularizace jater, depopulace jater,
- MeSH
- játra chemie MeSH
- lidé MeSH
- modely u zvířat MeSH
- prasata MeSH
- regenerativní lékařství metody MeSH
- tkáňové inženýrství * MeSH
- tkáňové podpůrné struktury MeSH
- transplantace jater MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
The in vivo rituximab effects in B cell malignancies are only partially understood. Here we analyzed in a large chronic lymphocytic leukemia (CLL) cohort (n = 80) the inter-patient variability in CLL cell count reduction within the first 24 h of rituximab administration in vivo, and a phenomenon of blood repopulation by malignant cells after anti-CD20 antibody therapy. Larger CLL cell elimination after rituximab infusion was associated with lower pre-therapy CLL cell counts, higher CD20 levels, and the non-exhausted capacity of complement-dependent cytotoxicity (CDC). The absolute amount of cell-surface CD20 molecules (CD20 density x CLL lymphocytosis) was a predictor for complement exhaustion during therapy. We also describe that a highly variable decrease in CLL cell counts at 5 h (88 %-2%) following rituximab infusion is accompanied in most patients by peripheral blood repopulation with CLL cells at 24 h, and in ∼20 % of patients, this resulted in CLL counts higher than before therapy. We provide evidence that CLL cells recrudescence is linked with i) CDC exhaustion, which leads to the formation of an insufficient amount of membrane attack complexes, likely resulting in temporary retention of surviving rituximab-opsonized cells by the mononuclear-phagocyte system (followed by their release back to blood), and ii) CLL cells regression from immune niches (CXCR4dimCD5bright intraclonal subpopulation). Patients with major peripheral blood CLL cell repopulation exhibited a longer time-to-progression after chemoimmunotherapy compared to patients with lower or no repopulation, suggesting chemotherapy vulnerability of CLL cells that repopulate the blood.
- MeSH
- chronická lymfatická leukemie krev farmakoterapie imunologie patologie MeSH
- cytotoxicita imunologická imunologie MeSH
- komplement imunologie MeSH
- lidé MeSH
- následné studie MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- rituximab terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Current standards in vascular reconstruction imply the use of autologous or synthetic material. Despite being standard, autologous grafts are limited by pathologies already affecting the patient and possible complications at the site of explantation, while synthetic grafts carry increased infection risks. Decellularized tissues have gained significant attention due to their potential for improving integration and functionality. The decellularization process removes cellular components while retaining the extracellular matrix, providing a scaffold that supports endothelial cell growth and minimizes immune rejection. Porcine decellularized vena cava is a promising candidate for vascular graft applications due to its structural similarity to human blood vessels and biocompatibility. In this study, we decellularized porcine vena cava with a combination of Triton X-100 and sodium dodecyl sulfate in four hours. We subsequently characterized the wall structure through histological stainings and proteomic analysis. Parameters such as wall thickness, intima-media layers thickness, collagen and elastin area fraction were quantified and compared. Moreover, decellularized veins were repopulated in vitro with human endothelial cells in static and dynamic conditions to verify the adhesion of human cells to the porcine scaffold and fully functionalize the lumen. An in-house-designed bioreactor was developed to seed endothelial cells on the lumen, mimicking the in vivo blood flow.
- MeSH
- bioreaktory MeSH
- decelularizovaná extracelulární matrix * chemie MeSH
- endoteliální buňky pupečníkové žíly (lidské) cytologie MeSH
- endoteliální buňky cytologie MeSH
- extracelulární matrix chemie MeSH
- kultivované buňky MeSH
- lidé MeSH
- prasata MeSH
- tkáňové inženýrství metody MeSH
- tkáňové podpůrné struktury * chemie MeSH
- venae cavae * cytologie chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: To study theoretically the impact on cell survival of the radionuclide uptake rate inside tumor cells for a single administration of a radiopharmaceutical. METHODS: The instantaneous-uptake model of O'Donoghue ["The impact of tumor cell proliferation in radioimmunotherapy," Cancer 73, 974-980 (1994)] for a proliferating cell population irradiated by an exponentially decreasing dose-rate is here extended to allow for the monoexponential uptake of the radiopharmaceutical by the targeted cells. The time derivative of the survival curve is studied in detail deducing an expression for the minimum of the surviving fraction and the biologically effective dose (BED). RESULTS: Surviving fractions are calculated over a parameter range that is clinically relevant and broad enough to establish general trends. Specifically, results are presented for the therapy radionuclides Y-90, I-131, and P-32, assuming uptake half-times 1-24 h, extrapolated initial dose-rates 0.5-1 Gy h(-1), and a biological clearance half-life of seven days. Representative radiobiological parameters for radiosensitive and rapidly proliferating tumor cells are used, with cell doubling time equal to 2 days and α-coefficient equal to 0.3 and 0.5 Gy(-1). It is shown that neglecting the uptake phase of the radiopharmaceutical (i.e., assuming instantaneous-uptake) results in a sizeable over-estimation of cell-kill (i.e., under-estimation of cell survival) even for uptake half-times of only a few hours. The differences between the exponential-uptake model and the instantaneous-uptake model become larger for high peak dose-rates, slow uptakes, and (slightly) for long-lived radionuclides. Moreover, the sensitivity of the survival curve on the uptake model was found to be higher for the tumor cells with the larger α-coefficient. CONCLUSIONS: The exponential-uptake rate of the radiopharmaceutical inside targeted cells appears to have a considerable effect on the survival of a proliferating cell population and might need to be considered in radiobiological models of tumor cell-kill in radionuclide therapy.
- MeSH
- analýza přežití MeSH
- biologické modely MeSH
- nádory farmakoterapie patofyziologie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky farmakokinetika farmakologie MeSH
- radiofarmaka farmakokinetika farmakologie MeSH
- radioizotopy fosforu farmakokinetika farmakologie MeSH
- radioizotopy jodu farmakokinetika farmakologie MeSH
- viabilita buněk účinky léků fyziologie MeSH
- vztah dávky záření a odpovědi MeSH
- yterbium farmakokinetika farmakologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
