BackgroundMesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy.MethodsA murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA using droplet digital PCR (ddPCR) allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values.ResultsImages of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1 level in the I/R injured liver than that in the control. Correspondingly, the ddPCR results illustrate a higher MSC concentration in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ddPCR results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses.DiscussionThe modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveal the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns.

Mesenchymal stem/stromal cells (MSCs) present a promising tool in cell‐based therapy for treatment of various diseases. Currently, optimization of treatment protocols in clinical studies is complicated by the variations in cell dosing, diverse methods used to deliver MSCs, and the variety of methods used for tracking MSCs in vivo. Most studies use a dose escalation approach, and attempt to correlate efficacy with total cell dose. Optimization could be accelerated through specific understanding of MSC distribution in vivo, long‐term viability, as well as their biological fate. While it is not possible to quantitatively detect MSCs in most targeted organs over long time periods after systemic administration in clinical trials, it is increasingly possible to apply pharmacokinetic modeling to predict their distribution and persistence. This Review outlines current understanding of the in vivo kinetics of exogenously administered MSCs, provides a critical analysis of the methods used for quantitative MSC detection in these studies, and discusses the application of pharmacokinetic modeling to these data. Finally, we provide insights on and perspectives for future development of effective therapeutic strategies using pharmacokinetic modeling to maximize MSC therapy and minimize potential side effects. Stem Cells Translational Medicine 2018;7:78–86

No abstract

No abstract

Cell membrane-coated nanoparticles are emerging as a new type of promising nanomaterials for immune evasion and targeted delivery. An underlying premise is that the unique biological functions of natural cell membranes can be conferred on the inherent physiochemical properties of nanoparticles by coating them with a cell membrane. However, the extent to which the membrane protein properties are preserved on these nanoparticles and the consequent bio–nano interactions are largely unexplored. Here, we synthesized two mesenchymal stem cell (MSC) membrane-coated silica nanoparticles (MCSNs), which have similar sizes but distinctly different stiffness values (MPa and GPa). Unexpectedly, a much lower macrophage uptake, but much higher cancer cell uptake, was found with the soft MCSNs compared with the stiff MCSNs. Intriguingly, we discovered that the soft MCSNs enabled the forming of a more protein-rich membrane coating and that coating had a high content of the MSC chemokine CXCR4 and MSC surface marker CD90. This led to the soft MCSNs enhancing cancer cell uptake mediated by the CD90/integrin receptor-mediated pathway and CXCR4/SDF-1 pathways. These findings provide a major step forward in our fundamental understanding of how the combination of nanoparticle elasticity and membrane coating may be used to facilitate bio–nano interactions and pave the way forward in the development of more effective cancer nanomedicines.

Background. Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of injury. However in vivo MSC distribution following intravenous transplantation remains poorly understood, potentially hampering the precise prediction and evaluation of therapeutic efficacy. Methods.A murine model of partial ischemia/reperfusion (I/R) is used to induce liver injury, increase the hepatic levels of SDF-1, and study in vivo MSC distribution. Hypoxia-preconditioning increases the expression of CXCR4 in human bone marrow-derived MSCs. Quantitative assays for human DNA allow us to examine the in vivo kinetics of intravenously infused human MSCs in mouse blood and liver. A mathematical model-based system is developed to characterize in vivo homing of human MSCs in mouse models with SDF-1 levels in liver and CXCR4 expression on the transfused MSCs. The model is calibrated to experimental data to provide novel estimates of relevant parameter values.Results. Images of immunohistochemistry for SDF-1 in the mouse liver with I/R injury show a significantly higher SDF-1level in the I/R injured liver than that in the control. Correspondingly, the ELISA results illustrate a higher MSC dose in the I/R injured liver than the normal liver. CXCR4 is overexpressed in hypoxia-preconditioned MSCs. An increased number of hypoxia-preconditioned MSCs in the I/R injured liver is observed from the ELISA results. The model simulations align with the experimental data of control and hypoxia-preconditioned human MSC distribution in normal and injured mouse livers, and accurately predict the experimental outcomes with different MSC doses.Discussion. The modelling results suggest that SDF-1 in organs is an effective in vivo attractant for MSCs through the SDF-1/CXCR4 axis and reveals the significance of the SDF-1/CXCR4 chemotaxis on in vivo homing of MSCs, especially under hypoxic preconditioning. The impact of the liver and MSC conditions on passive homing is small. This in vivo modelling approach allows qualitative characterization and prediction of the MSC homing to normal and injured organs on the basis of clinically accessible variables, such as the MSC dose and SDF-1 concentration in blood. This model could also be adapted to abnormal conditions and/or other types of circulating cells to predict in vivo homing patterns. PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.27144v1 | CC BY 4.0 Open Access | rec22 23 24 ABSTRACT 25 Background. Mesenchymal stem/stromal cells (MSCs) are a promising tool for cell-based 26 therapies in the treatment of tissue injury. The stromal cell-derived factor-1 (SDF-1)/CXC 27 chemokine receptor 4 (CXCR4) axis plays a significant role in directing MSC homing to sites of 28 injury. However in vivo MSC distribution following intravenous transplantation remains poorly 29 understood, potentially hampering the precise predic...

No abstract

Background and Aims: The malignant potential of gallbladder lesions is debated, and there is limited guidance on surveillance. Predicting their risk of malignancy could help clinicians manage and potentially improve prognosis. We evaluated the independent and joint effects of metabolic syndrome components on the risk of malignancy among patients with gallbladder lesions. Methods: Using a multicenter database, consecutive patients with pathologically confirmed gallbladder lesions between 2012 and 2019 were identified. Univariate and multivariate logistic regression analyses were used to evaluate the effects of metabolic syndrome components (diabetes, hypertension, dyslipidemia, obesity) as additive or combined indicators for the risk of malignancy. Unadjusted and adjusted odds ratios were calculated. Results: Of the 625 patients, 567 patients were identified with benign gallbladder lesions and 58 patients with gallbladder cancer (GBC). Among all metabolic syndrome components, the proportion of GBC patients with dyslipidemia (63.8%) was significantly greater than benign gallbladder polyps (42.2%, P = 0.002). In multivariate logistic regression analysis, dyslipidemia was associated with a 2.67-fold increase in the risk of GBC (95% confidence interval 1.17-6.09). Dyslipidemia is an independent risk factor for malignancy (adjusted odds ratio 2.164, 95% confidence interval 1.165-4.021), regardless of whether the other risk factors and metabolic syndrome components are combined. Dyslipidemia (adjusted odds ratio 2.164, 95% confidence interval 1.165-4.021) and decreased high-density lipoprotein (HDL, adjusted odds ratio 3.035, 95% confidence interval 1.645-5.600) were closely associated with increased risk of malignancy. Conclusions: Dyslipidemia is associated with a 2.67-fold increase in the risk of malignancy, regardless of the presence of other metabolic syndrome components. Dyslipidemia is an independent risk factor for malignancy in patients with gallbladder lesions.