Impaired wound healing remains a challenge to date and causes debilitating effects with tremendous suffering. Recent advances in tissue engineering approaches in the area of cell therapy have provided promising treatment options to meet the challenges of impaired skin wound healing such as diabetic foot ulcers. Over the last few years, stem cell therapy has emerged as a novel therapeutic approach for various diseases including wound repair and tissue regeneration. Several different types of stem cells have been studied in both preclinical and clinical settings such as bone marrow-derived stem cells, adipose-derived stem cells (ASCs), circulating angiogenic cells (e.g., endothelial progenitor cells), human dermal fibroblasts, and keratinocytes for wound healing. Adipose tissue is an abundant source of mesenchymal stem cells, which have shown an improved outcome in wound healing studies. ASCs are pluripotent stem cells with the ability to differentiate into different lineages and to secrete paracrine factors initiating tissue regeneration process. The abundant supply of fat tissue, ease of isolation, extensive proliferative capacities ex vivo, and their ability to secrete pro-angiogenic growth factors make them an ideal cell type to use in therapies for the treatment of nonhealing wounds. In this review, we look at the pathogenesis of chronic wounds, role of stem cells in wound healing, and more specifically look at the role of ASCs, their mechanism of action and their safety profile in wound repair and tissue regeneration.

Ion-sensitive responsive polymers are prepared under fully aqueous conditions using controlled radical polymerization. Variations in comonomer content and sequence lead to temperature and salt-dependent solution behavior, with cloud-points ranging by +/-40 degrees C following addition of Hofmeister series salts. A "hybrid" block copolymer, composed of a statistical sequence of monomers tipped with a hydrophilic block, formed stable micelle-like assemblies that exhibited burst release of an encapsulated model drug in response to addition of a kosmotrope, Na2SO4, at room temperature.

The Ipl (Tssc3) gene lies in an extended imprinted region of distal mouse chromosome 7, which also contains the Igf2 gene. Expression of Ipl is highest in placenta and yolk sac, where its mRNA is derived almost entirely from the maternal allele. Ipl encodes a small cytoplasmic protein with a pleckstrin-homology (PH) domain. We constructed two lines of mice with germ-line deletions of this gene (Ipl neo and Ipl loxP ) and another line deleted for the similar but nonimprinted gene Tih1. All three lines were viable. There was consistent overgrowth of the Ipl-null placentas, with expansion of the spongiotrophoblast. These larger placentas did not confer a fetal growth advantage; fetal size was normal in Ipl nulls with the Ipl neo allele and was decreased slightly in nulls with the Ipl loxP allele. When bred into an Igf2 mutant background, the Ipl deletion partially rescued the placental but not fetal growth deficiency. Neither fetal nor placental growth was affected by deletion of Tih1. These results show a nonredundant function for Ipl in restraining placental growth. The data further indicate that Ipl can act, at least in part, independently of insulin-like growth factor-2 signaling. Thus, genomic imprinting regulates multiple pathways to control placental size. The Ipl gene, also known as Tssc3, lies on distal chromosome 7 of the mouse and human chromosome 11p15.5 (1, 2). This region contains multiple imprinted genes clustered in 1 Mb of DNA. Two of these, p57 Kip2 (Cdkn1c) and Igf2, control fetal and placental growth in mice (3-7) and humans (8). Similar to these genes, Ipl is highly expressed in the extraembryonic tissues (1), but in contrast to these genes, Ipl is expressed only weakly in the embryo proper (1, 9). Ipl encodes a cytoplasmic protein with a pleckstrin-homology (PH) domain (9), thus by analogy with other PH-domain proteins it may modulate cell signaling, intracellular trafficking, or other processes that depend on phosphatidylinositol lipid second messengers. Ipl has two close relatives: TDAG51 and Tih1. Of these genes, Tih1 is most similar to Ipl (9). Tih1 is located in a nonimprinted region of mouse chromosome 1, and it is expressed biallelically (9). To determine the function of Ipl and to accumulate data relevant to the biological rationale for imprinting, we created mice with germ-line deletions of Ipl and Tih1. Materials and MethodsGene Deletions, Genotyping, and Gene Expression. To make the Ipl neo targeting vector, a 5-kb 5Ј genomic NotI restriction fragment and a 6-kb 3Ј EcoRI͞XbaI fragment flanking Ipl were ligated upstream and downstream of Pgk-Neo in pPNT1, yielding pPNT-Ipl. To make the Ipl loxP targeting vector, the Pgk-Neo cassette of pPNT-⌬Ipl was replaced by that from pLNL, which includes flanking loxP sites. To verify homologous recombination, we used genomic PCR products upstream and downstream of the 5Ј and 3Ј cassettes. Recombination of the loxP sites was induced by crossing to HSP-Cre transgenic mice (10). The Ipl deletions (encompassing nucleotides 77,444-78,990 of GenBank a...

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Stem cells have shown substantial promise for various diseases in preclinical and clinical trials. However, low cell engraftment rates significantly limit the clinical translation of stem cell therapeutics. Numerous injectable hydrogels have been developed to enhance cell retention. Yet, the design of an ideal material with tunable properties that can mimic different tissue niches and regulate stem cell behaviors remains an unfulfilled promise. Here, an injectable poly(ethylene glycol) (PEG)-gelatin hydrogel is designed with highly tunable properties, from a multifunctional PEG-based hyperbranched polymer and a commercially available thiolated gelatin. Spontaneous gelation occurs within about 2 min under the physiological condition. Murine adiposederived stem cells (ASCs) can be easily encapsulated into the hydrogel, which supports ASC growth and maintains their stemness. The hydrogel mechanical properties, biodegradability, and cellular responses can be finely controlled by changing hydrogel formulation and cell seeding densities. An animal study shows that the in situ formed hydrogel significantly improves cell retention, enhances angiogenesis, and accelerates wound closure using a murine wound healing model. These data suggest that injectable PEG-gelatin hydrogel can be used for regulating stem cell behaviors in 3D culture, delivering cells for wound healing and other tissue regeneration applications.

The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting of BRD4 bromodomains by small molecule inhibitors has proven to be an effective means to disrupt aberrant transcriptional programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, and orally available BET/BRD4 bromodomain inhibitor possessing a bivalent binding mode. Unlike previously described monovalent inhibitors, AZD5153 ligates two bromodomains in BRD4 simultaneously. The enhanced avidity afforded through bivalent binding translates into increased cellular and antitumor activity in preclinical hematologic tumor models. In vivo administration of AZD5153 led to tumor stasis or regression in multiple xenograft models of acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma. The relationship between AZD5153 exposure and efficacy suggests that prolonged BRD4 target coverage is a primary efficacy driver. AZD5153 treatment markedly affects transcriptional programs of MYC, E2F, and mTOR. Of note, mTOR pathway modulation is associated with cell line sensitivity to AZD5153. Transcriptional modulation of MYC and HEXIM1 was confirmed in AZD5153-treated human whole blood, thus supporting their use as clinical pharmacodynamic biomarkers. This study establishes AZD5153 as a highly potent, orally available BET/BRD4 inhibitor and provides a rationale for clinical development in hematologic malignancies. Mol Cancer Ther; 15(11); 2563-74. ©2016 AACR.

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Hyperbranched polymers with both highly branched structures and numerous vinyl functional groups have been synthesized via reversible activation/deactivation controlled polymerization of multifunctional vinyl monomers. By controlling the competition between propagation and reversible termination using a deactivation enhanced method, the growth rate of polymer chains is decreased and the onset of gelation is prevented until the system has achieved much higher levels of conversion than has previously been reported for nonenhanced systems. Here, we demonstrate this strategy by synthesizing highly branched, irregular dendritic polymers with a multiplicity of reactive functionalities such as vinyl and halogen functional groups, and controlled chain structure via deactivation enhanced atom transfer radical polymerization (ATRP) of a commercially available multifunctional vinyl monomerdivinylbenzene (DVB) and ethylene glycol dimethacrylate (EGDMA).