The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)

Purpose: Sipuleucel-T, an autologous cellular immunotherapy, was investigated in a randomized, double-blind, controlled trial to determine its biologic activity in androgen-dependent prostate cancer (ADPC).Experimental Design: Patients with prostate cancer detectable by serum prostate-specific antigen (PSA) following radical prostatectomy received 3 to 4 months of androgen suppression therapy, and were then randomized (2:1) to receive sipuleucel-T (n ¼ 117) or control (n ¼ 59). The primary endpoint was time to biochemical failure (BF) defined as serum PSA 3.0 ng/mL. PSA doubling time (PSADT), time to distant failure, immune response, and safety were also evaluated.Results: Median time to BF was 18.0 months for sipuleucel-T and 15.4 months for control (HR ¼ 0.936, P ¼ 0.737). Sipuleucel-T patients had a 48% increase in PSADT following testosterone recovery (155 vs. 105 days, P ¼ 0.038). With only 16% of patients having developed distant failure, the treatment effect favored sipuleucel-T (HR ¼ 0.728, P ¼ 0.421). The most frequent adverse events in sipuleucel-T patients were fatigue, chills, and pyrexia. Immune responses to the immunizing antigen were greater in sipuleucel-T patients at Weeks 4 and 13 (P < 0.001, all) and were sustained prior to boosting as measured in a subset of patients a median of 22.6 months (range: 14.3-67.3 months) following randomization.Conclusions: No significant difference in time to BF could be shown. The finding of increased PSADT in the sipuleucel-T arm is consistent with its biologic activity in ADPC. Long-term follow-up will be necessary to determine if clinically important events, such as distant failure, are affected by therapy. Treatment was generally well tolerated. Clin Cancer Res; 17(13); 4558-67. Ó2011 AACR.

The pluripotent mesenchymal stem cells (MSC) are common precursors to adipocytes and osteoblasts. Large numbers of extracellular and intracellular signals and transcription factors moderate adipogenesis and osteoblastogenesis. Importantly, between adipogenic and osteogenic lineage commitment and differentiation, differentiation of MSCs into one lineage will inhibit their differentiation toward the other lineage. This balance is regulated by numerous signaling pathways. As we know, the peroxisome-proliferator-activated receptor-γ (PPAR-γ) and Wnt/β-catenin pathway are regarded as the master moderators of adipogenesis and osteogenesis. Moreover, governing the differentiation of MSCs to adipogenesis and osteoblastogenesis has significant implications in diverse areas of human health, from obesity to regenerative medicine to osteoporosis. Rivalry roles have been reported of the two pathways since the downstream products activated by Wnt-5a repress PPAR-γ transactivation through the H3K9 histone methyltransferase protein complexes. This review will discuss the inductive and inhibitive role of PPAR-γ in adipogenesis and osteoblastogenesis respectively, as well as the canonical Wnt/β-catenin pathway.

Nanotechnology employs multifunctional engineered materials in the nanoscale range that provides many opportunities for translational stem cell research and therapy. Here, a cell‐penetrating peptide (virus‐1 transactivator of transcription)–conjugated, porous silicon nanoparticle (TPSi NP) loaded with the Wnt3a protein to increase both the cell survival rate and the delivery precision of stem cell transplantation via a combinational theranostic strategy is presented. The TPSi NP with a pore size of 10.7 nm and inorganic framework enables high‐efficiency loading of Wnt3a, prolongs Wnt3a release, and increases antioxidative stress activity in the labeled mesenchymal stem cells (MSCs), which are highly beneficial properties for cell protection in stem cell therapy for myocardial infarction. It is confirmed that the intracellular aggregation of TPSi NPs can highly amplify the acoustic scattering of the labeled MSCs, resulting in a 2.3‐fold increase in the ultrasound (US) signal compared with that of unlabeled MSCs. The translational potential of the designed nanoagent for real‐time US imaging–guided stem cell transplantation is confirmed via intramyocardial injection of labeled MSCs in a nude mouse model. It is proposed that the intracellular aggregation of protein drug–loaded TPSi NPs could be a simple but robust strategy for improving the therapeutic effect of stem cell therapy.

Although hydrogels can be applied in mimicking the native extracellular matrix environment, they generally suffer from weak mechanical properties, as well as the lack of a sustained supply of nutrients or simulants to maintain cell functions, which severely limits their further practical applications. Aiming to address the aforementioned issues, a novel reinforced nanocomposite hydrogel (NC gel) is developed, which is composed of gelatin methacryloyl (GelMA) and carboxyl-modified mesoporous silica nanoparticles (MSNs-COOH) together with pinacidil loading. The mechanical properties and pore size of the NC gel can be tunable with the addition of different amounts of MSNs-COOH. In addition, mesoporous channels of MSNs-COOH endow the prepared NC gel with good performance in piancidil loading and longterm sustained release, which greatly promotes the viability and adhesion of bone marrow mesenchymal stem cells (BMSCs) and achieves the long-term cell adhesion, spreading and viability of encapsulated BMSC cells in 7 days. This NC gel platform shows great promise for tissue engineering applications, including functional integration and efficient differentiation of stem cells upon transplantation.

Platelet-derived growth factor (PDGF) B-chain and PDGF receptor ␤ (PDGFR ␤) are essential for glomerulogenesis. Mice deficient in PDGF B-chain or PDGFR ␤ exhibit an abnormal glomerular phenotype characterized by total lack of mesangial cells. In this study, we localized PDGFR ␤ in the developing rat kidney and explored the biological effects of PDGF in metanephric mesenchymal cells in an attempt to determine the mechanism by which PDGF regulates mesangial cell development. Immunohistochemical and in situ hybridization studies of rat embryonic kidneys reveal that PDGFR ␤ localizes to undifferentiated metanephric mesenchyme and is later expressed in the cleft of the comma-shaped and S-shaped bodies and in more mature glomeruli in a mesangial distribution. We also isolated and characterized cells from rat metanephric mesenchyme. Metanephric mesenchymal cells express vimentin and ␣-smooth muscle actin but not cytokeratin. These cells also express functional PDGFR ␤, as demonstrated by autophosphorylation of the receptor as well as activation of phosphatidylinositol 3 kinase in response to PDGF B-chain homodimer. PDGF B-chain also induces migration and proliferation of metanephric mesenchymal cells. Taken together with the fact that PDGF Bchain is expressed in the glomerular epithelium and mesangial area, as demonstrated in the human embryonic kidney, we suggest that PDGF B-chain acts in a paracrine fashion to stimulate the migration and proliferation of mesangial cell precursors from undifferentiated metanephric mesenchyme to the mesangial area. PDGF B-chain also likely stimulates proliferation of mesangial cell precursors in an autocrine fashion once these cells migrate to the glomerular tuft. Platelet-derived growth factor receptor ␤ (PDGFR ␤)1 is abundantly expressed in a variety of mesenchymal cells in mid gestation embryo. In human embryo at 54 -105 days of gestation, immunohistochemical studies demonstrated that PDGFR ␤ is expressed in the undifferentiated metanephric mesenchyme and in maturing glomeruli, whereas platelet-derived growth factor (PDGF) B-chain is expressed in epithelial cells and the mesangium of maturing glomeruli (1). This spatial and temporal distribution of PDGF B-chain and PDGFR ␤ suggests a role for PDGF in the development of glomerular cells, including mesangial cells. The roles of PDGF B-chain and PDGFR ␤ in mesangial cell development have been conclusively demonstrated in two recent studies utilizing mice carrying mutations in either PDGF B-chain or PDGFR ␤. The kidney phenotype in these mice exhibit glomeruli that lack mesangial cells and structural disorganization of the glomerular capillaries (2, 3).PDGF B-chain is a potent mitogen for most if not all mesenchymal cells. In the mature adult kidney, platelet-derived growth factor B-chain homodimer (PDGF BB) is mitogenic for mesangial cells, interstitial fibroblasts, and smooth muscle cells. PDGF also stimulates mesangial cell migration in vitro (4) and has been implicated as a mediator in inflammatory and progressive glomerular and int...

S U M M A R Y Glomerular endothelial and mesangial cells may originate from the metanephric mesenchyme. We used the MAb Thy1.1, a mesangial cell marker in the adult rat kidney, and rat endothelial cell markers MAb RECA-1, MAb PECAM-1 (CD31), and MAb Flk-1 as potential markers to characterize the spatial and temporal distribution of mesangial and endothelial cell precursors during nephrogenesis in the rat. At early stages of glomerulogenesis, RECA-1-and Thy1.1-positive cells were detected in the metanephric blastema at 14 days post conception (dpc) embryos and 15 dpc, respectively, with Thy1.1 expression in cells surrounding the ureteric bud. At 17 and 18 dpc, both RECA-1-and Thy1.1-positive cells were found in the cleft of the S-shaped bodies and in the capillary loops of maturing glomeruli. Double staining for BrdU, a marker of proliferation, and for RECA-1 or BrdU and Thy1.1 also localize in the cleft of S-shaped bodies and in glomerular capillary loops at later stages of development. PDGFR ␤ co-localizes in cells expressing endothelial or mesangial markers. The data suggest that endothelial and mesangial cell precursors share common markers during the course of glomerulogenesis and that full differentiation of these cells occurs at late stages of glomerular maturation. Thy1.1-and RECA-1-positive cells may be derived from the metanephric blastemal cells at early stages of kidney development. A subpopulation of these Thy1.1-or RECA-1-positive cells may be precursors that can migrate into the cleft of comma and S-shaped bodies and proliferate in situ to form glomerular capillary tufts.

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