Induced pluripotent stem cell derived cardiac models: effects of Thymosin ß4.

INTRODUCTION: The establishment of induced pluripotent stem cells (iPSCs) and cardiomyocytes differentiated from them generated a new platform to study pathophysiological processes and to generate drug screening platforms and iPSC-derived tissues as therapeutic agents. Although major advances have been made in iPSC-reprogramming, cardiac differentiation and EHT production, reprogramming efficiency and the maturity of iPSC-CMs need to be further improved. AREAS COVERED: In this review, the authors summarize the current state of the field of iPSC research, the methodology of cardiac differentiation of iPSCs, the use of iPSC-CMs as disease models and toxicity screening platforms, and the potential of EHTs as therapeutic agents. The authors furthermore highlight the mechanisms by which Thymosin ß4 might enhance the production of iPSC-CMs and EHTs to improve their maturity and performance. EXPERT OPINION: iPSCs derived cardiomyocytes and EHTs represent a still young research field with many problems and pitfalls that need to be resolved to realize the full potential of iPSC-CMs and EHTs. Given that Thymosin ß4 directly enhances cardiac differentiation while also promoting angiogenic sprouting and vessel maturation, Tß4 might be of particular interest as a novel agent in tackling the difficulty of iPSC-CMs and engineered heart tissue grafts.

In vivo monitoring of sorafenib therapy effects on experimental prostate carcinomas using dynamic contrast-enhanced MRI and macromolecular contrast media.

PURPOSE: To investigate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with macromolecular contrast media (MMCM) to monitor the effects of the multikinase inhibitor sorafenib on subcutaneous prostate carcinomas in rats with immunohistochemical validation. MATERIALS AND METHODS: Copenhagen rats, implanted with prostate carcinoma allografts, were randomized to the treatment group (n = 8) or the control group (n = 8). DCE-MRI with albumin-(Gd-DTPA)35 was performed at baseline and after 1 week using a clinical 3-Tesla system. The treatment group received sorafenib, 10 mg/kg body weight daily. Kinetic analysis yielded quantitative parameters of tumor endothelial permeability-surface area product (PS; ml/100 ml/min) and fractional blood volume (Vb, %). Tumors were harvested on day 7 for immunohistochemical analysis. RESULTS: In sorafenib-treated tumors, PS (0.62 ± 0.20 vs 0.08 ± 0.09 ml/100 ml/min; P < 0.01) and Vb (5.1 ± 1.0 vs 0.56 ± 0.48%; P < 0.01) decreased significantly from day 0 to day 7. PS showed a highly significant inverse correlation with tumor cell apoptosis (TUNEL; r = -0.85, P < 0.001). Good, significant correlations of PS were also observed with tumor cell proliferation (Ki-67; r = 0.67, P < 0.01) and tumor vascularity (RECA-1; r = 0.72, P < 0.01). MRI-assayed fractional blood volume Vb showed a highly significant correlation with tumor vascularity (RECA-1; r = 0.87, P < 0.001) and tumor cell proliferation (Ki-67; r = 0.82, P < 0.01). CONCLUSION: Results of DCE-MRI with MMCM demonstrated good, significant correlations with the immunohistochemically assessed antiangiogenic, antiproliferative, and proapoptotic effects of a 1-week, daily treatment course of sorafenib on experimental prostate carcinoma allografts.

Dynamic contrast-enhanced computed tomography imaging biomarkers correlated with immunohistochemistry for monitoring the effects of sorafenib on experimental prostate carcinomas.

OBJECTIVES: To investigate dynamic contrast-enhanced computed tomography (DCE-CT) for monitoring the effects of sorafenib on experimental prostate carcinomas in rats by quantitative assessments of tumor microcirculation parameters with immunohistochemical validation. MATERIAL AND METHODS: Prostate carcinoma allografts (MLLB-2) implanted subcutaneously in male Copenhagen rats (n=16) were imaged at baseline and after a 1-week treatment course of sorafenib using DCE-CT with iopromide (Ultravist 370, Bayer Pharma, Berlin, Germany) on a dual-source 128-slice CT (Somatom Definition FLASH, Siemens Healthcare, Forchheim, Germany). Scan parameters were as follows: detector width, 38.4 mm; contrast agent volume, 2 mL/kg bodyweight; injection rate, 0.5 mL/s; scan duration, 90 seconds; and temporal resolution, 0.5 seconds. The treatment group (n=8) received daily applications of sorafenib (10 mg/kg bodyweight) via gavage. Quantitative parameters of tumor microcirculation (plasma flow, mL/100 mL/min), endothelial permeability-surface area product (PS, mL/100 mL/min), and tumor vascularity (plasma volume, %) were calculated using a 2-compartment uptake model. DCE-CT parameters were correlated with immunohistochemical assessments of tumor vascularity (RECA-1), cell proliferation (Ki-67), and apoptosis (TUNEL). RESULTS: Sorafenib significantly (P < 0.05) suppressed tumor perfusion (25.1 ± 9.8 to 9.5 ± 6.0 mL/100 mL/min), tumor vascularity (15.6% ± 11.4% to 5.4% ± 2.1%), and PS (8.7 ± 4.5 to 2.7 ± 2.5 mL/100 mL/min) in prostate carcinomas during the treatment course. Immunohistochemistry revealed significantly lower tumor vascularity in the therapy group than in the control group (RECA-1; 181 ± 24 vs. 314 ± 47; P < 0.05). In sorafenib-treated tumors, significantly more apoptotic cells (TUNEL; 7132 ± 3141 vs. 3722 ± 1445; P < 0.05) and significantly less proliferating cells (Ki-67; 9628 ± 1.298 vs. 17,557 ± 1446; P < 0.05) were observed than those in the control group. DCE-CT tumor perfusion correlated significantly (P < 0.05) with tumor cell proliferation (Ki-67; r=0.55). DCE-CT tumor vascularity correlated significantly (P < 0.05) with immunohistochemical tumor cell apoptosis (TUNEL; r=-0.59) and tumor cell proliferation (Ki-67; r=0.68). DCE-CT endothelial PS correlated significantly (P < 0.05) with immunohistochemical tumor cell apoptosis (TUNEL; r=-0.6) and tumor vascularity (RECA-1; r=0.53). While performing corrections for multiple comparisons, we observed a significant correlation only between DCE-CT tumor vascularity (RECA-1) and tumor cell proliferation (Ki-67). CONCLUSION: Sorafenib significantly suppressed tumor perfusion, tumor vascularity, and PS quantified by DCE-CT in experimental prostate carcinomas in rats. These functional CT surrogate markers showed moderate correlations with antiangiogenic, antiproliferative, and proapoptotic effects observed by immunohistochemistry. DCE-CT may be applicable for the quantification of noninvasive imaging biomarkers of therapy response to antiangiogenic therapy.