BackgroundHuman mesenchymal stem cells (MSCs) have drawn much attention in the field of regenerative medicine for their immunomodulatory and anti-inflammatory effects. MSCs possess specific tumor-oriented migration and incorporation highlighting the potential for MSCs to be used as an ideal carrier for anticancer agents. Bone marrow is the main source of MSCs for clinical applications. MSCs tracking in vivo is a critical component of the safety and efficacy evaluation of therapeutic cell products; therefore, cells must be labeled with contrast agents to enable visualization of the MSCs migration in vivo. Due to their unique properties, quantum dots (QDs) are emerging as optimal tools in long-term MSC optical imaging applications. The aim of this study was to investigate the uptake dynamics, cytotoxity, subcellular and extracellular distribution of non-targeted carboxylated quantum dots in human bone marrow MSCs at different cell growing densities.ResultsQDs had no negative impact on MSC viability throughout the experiment and accumulated in all observed cells efficiently; however, in some MSCs QDs induced formation of lipid droplets. At low cell growing densities QDs distribute within MSCs cytoplasm already after 1 h of incubation reaching saturation after 6 h. After 24 h QDs localize mainly in the perinuclear region of the cells in endosomes. Interestingly, in more confluent culture QDs localize mostly outside MSCs. QDs abundantly mark MSC long filopodia-like structures attaching neighboring cells. At high cell density cultivation, we for the first time demonstrated that carboxylated QDs localize in human bone marrow MSC extracellular matrix. Moreover, we observed that average photoluminescence lifetime of QDs distributed in extracellular matrix are longer than lifetimes of QDs entrapped in endocytic vesicles; thus, for the first time showing the possibility to identify and distinguish localization of QDs in various extracellular and intracellular structures using fluorescence-lifetime imaging microscopy without additional staining assays.ConclusionCarboxylated QDs can be used as nonspecific and effective dye for staining of human bone marrow MSCs and their specific extracellular structures. These results are promising in fundamental stem cell biology as well as in cellular therapy, anticancer drug delivery and tissue engineering.Electronic supplementary materialThe online version of this article (10.1186/s12951-019-0470-6) contains supplementary material, which is available to authorized users.
Principles of molecular self-assembly into giant hierarchical structures of hundreds of micrometers in size are studied in aggregates of meso-tetra(4-sulfonatophenyl)porphine (TPPS4). The aggregates form a central tubular core, which is covered with radially protruding filamentous non-branching aggregates. The filaments cluster and orient at varying angles from the core surface and some filaments form bundles. Due to shape resemblance, the structures are termed giant sea urchin (GSU) aggregates. Spectrally resolved fluorescence microscopy reveals J- and H-bands of TPPS4 aggregates in both the central core and the filaments. The fluorescence of the core is quenched while filaments exhibit strong fluorescence. Upon drying, the filament fluorescence gets quenched while the core is less affected, showing stronger relative fluorescence. Fluorescence-detected linear dichroism (FDLD) microscopy reveals that absorption dipoles corresponding to J-bands are oriented along the filament axis. The comparison of FDLD with scanning electron microscopy (SEM) reveals the structure of central core comprised of multilayer ribbons, which wind around the core axis forming a tube. Polarimetric second-harmonic generation (SHG) and third-harmonic generation microscopy exhibits strong signal from the filaments with nonlinear dipoles oriented close to the filament axis, while central core displays very low SHG due to close to centrosymmetric organization. Large chiral nonlinear susceptibility points to helical arrangement of the filaments. The investigation shows that TPPS4 molecules form distinct aggregate types, including chiral nanotubes and nanogranular aggregates that associate into the hierarchical GSU structure, prototypical to complex biological structures. The chiral TPPS4 aggregates can serve as harmonophores for nonlinear microscopy.
Nanotechnology has emerged as a promising solution to permanent elimination of cancer. However, nanoparticles themselves lack specificity to tumors. Due to enhanced migration to tumors, mesenchymal stem cells (MSCs) were suggested as cell-mediated delivery vehicles of nanoparticles. In this study, we have constructed a complex composed of photoluminescent quantum dots (QDs) and a photosensitizer chlorin e6 (Ce6) to obtain multifunctional nanoparticles, combining cancer diagnostic and therapeutic properties. QDs serve as energy donorsexcited QDs transfer energy to the attached Ce6 via Forster resonance energy transfer, which in turn generates reactive oxygen species. Here, the physicochemical properties of the QD-Ce6 complex and singlet oxygen generation were measured, and the stability in protein-rich media was evaluated, showing that the complex remains the most stable in proteinfree medium. In vitro studies on MSC and cancer cell response to the QD-Ce6 complex revealed the complex-loaded MSCs' potential to transport theranostic nanoparticles and induce cancer cell death. In vivo studies proved the therapeutic efficacy, as the survival of tumor-bearing mice was statistically significantly increased, while tumor progression and metastases were slowed down.
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