Abstract Pancreatic islet transplantation is an attractive option for treatment of type 1 diabetes mellitus but maintaining long term islet function remains challenging. Mesenchymal stromal cells ...(MSCs), derived from bone marrow or other sources, are being extensively investigated in the clinical setting for their immunomodulatory and tissue regenerative properties. Indeed, MSCs have been already tested in some feasibility studies in the context of islet transplantation. MSCs could be utilized to improve engraftment of pancreatic islets by suppressing inflammatory damage and immune mediated rejection. In addition to their immunomodulatory effects, MSCs are known to provide a supportive microenvironmental niche by secreting paracrine factors and depositing extracellular matrix. These properties could be used for in vivo co-transplantation to improve islet engraftment, or for in vitro co-culture to prime freshly isolated islets prior to implantation. Further, tissue specific pancreatic islet derived MSCs may open new opportunities for its use in islet transplantation as those cells might be more physiological to pancreatic islets.
Abstract
Background
Components of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy ...including the proteasome inhibitor bortezomib. However, functional distinctions between BMSCs in MM patients and those in disease-free marrow are not completely understood. We and other investigators have recently reported that NF-κB activity in primary MM cells is largely resistant to the proteasome inhibitor bortezomib, and that further enhancement of NF-κB by BMSCs is similarly resistant to bortezomib and may mediate resistance to this therapy. The mediating factor(s) of this bortezomib-resistant NF-κB activity is induced by BMSCs is not currently understood.
Results
Here we report that BMSCs specifically derived from MM patients are capable of further activating bortezomib-resistant NF-κB activity in MM cells. This induced activity is mediated by soluble proteinaceous factors secreted by MM BMSCs. Among the multiple factors evaluated, interleukin-8 was secreted by BMSCs from MM patients at significantly higher levels compared to those from non-MM sources, and we found that IL-8 contributes to BMSC-induced NF-κB activity.
Conclusions
BMSCs from MM patients uniquely enhance constitutive NF-κB activity in MM cells via a proteinaceous secreted factor in part in conjunction with IL-8. Since NF-κB is known to potentiate MM cell survival and confer resistance to drugs including bortezomib, further identification of the NF-κB activating factors produced specifically by MM-derived BMSCs may provide a novel biomarker and/or drug target for the treatment of this commonly fatal disease.
Current immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most ...hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment.
First, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models,
and
xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice.
We demonstrate that percentage of LILRB1
NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1
NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors,
and
.
Our results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.
During the past several years, multipotent mesenchymal stromal cells (MSCs) have rapidly moved from in vitro and animal studies into clinical trials as a therapeutic modality potentially applicable ...to a wide range of disorders. It has been proposed that ex vivo culture-expanded MSCs exert their tissue regeneration potential through their immunomodulatory and anti-inflammatory properties, and paracrine effects more than their ability to differentiate into multiple tissue lineages. Since extracellular matrix (ECM) deposition and tissue support is also one of many physiological roles of MSCs, there is increasing interest in their potential use for tissue engineering, particularly in combination with ECM-based scaffolds such as hyaluronic acid (HA). We investigated the effect of MSCs on immunophenotype of macrophages in the presence of an HA-hydrogel scaffold using a unique 3D coculture system. MSCs were encapsulated in the hydrogel and peripheral blood CD14+ monocyte-derived macrophages plated in direct contact with the MSC-gel construct. To determine the immunophenotype of macrophages, we looked at the expression of cell surface markers CD14, CD16, CD206, and human leukocyte antigen (HLA)-DR by flow cytometry. MSCs and macrophages cultured on the HA-hydrogel remained viable and were able to be recovered from the construct. There was a significant difference in the immunophenotype observed between monocyte-derived macrophages cultured on the HA scaffold compared to tissue culture polystyrene. Macrophages cultured on gels with MSCs expressed lower CD16 and HLA-DR with higher expression of CD206, indicating the least inflammatory profile overall, compatible with the immunophenotype of alternatively activated macrophages. Development of macrophages, with this immunophenotype, upon interaction with the MSC-hydrogel constructs may play a potentially significant role in tissue repair when using a cellular-biomaterial therapeutic approach.
In this study, we compared MSCs from breast and abdominal tissue in terms of their expression of genes deemed important in the support of breast cancer growth and their effect on gene profile of ...macrophages after coculture. In addition, we investigated the role of MSCs, alone or in combination with macrophages, on proliferation of breast cancer cell lines. Our results show that MSCs derived from breast and abdominal adipose tissues have a comparable gene expression profile, have similar effect on gene expression of macrophages, and are comparable in supporting breast cancer cell line proliferation.
Objectives/Hypothesis:
Mesenchymal stem cells (MSCs) originally isolated from bone marrow (BM), are fibroblast‐looking cells that are now assumed to be present in the stromal component of many ...tissues. MSCs are characterized by a certain set of criteria, including their growth culture characteristics, a combination of cell surface markers, and the ability to differentiate along multiple mesenchymal tissue lineages. We hypothesized that human vocal fold fibroblasts (hVFF) isolated from the lamina propria meet the criteria established to define MSCs and are functionally similar to MSCs derived from BM and adipose tissue.
Study Design:
In vitro study.
Methods:
hVFF were previously derived from human vocal fold tissues. MSCs were derived from adipose tissue (AT), and BM of healthy donors based on their attachment to culture dishes and their morphology and expanded in culture. Cells were analyzed for standard cell surface markers identified on BM‐derived MSCs and the ability to differentiate into cells of mesenchymal lineage (i.e., fat, bone, and cartilage). We investigated the immunophenotype of these cells before and after interferon‐γ (INF‐γ) stimulation.
Results:
hVFF displayed cell surface markers and multipotent differentiation capacity characteristic of MSCs. Furthermore, these cells exhibited similar patterns of expression of human leukocyte antigen and costimulatory molecules, after stimulation with INF‐γ compared to MSCs derived from BM and AT.
Conclusions:
Based on our findings, hVFF derived from lamina propria have the same cell surface markers, immunophenotypic characteristics, and differentiation potential as BM‐ and AT‐derived MSCs. We propose that vocal fold fibroblasts are MSCs resident in the vocal fold lamina propria. Laryngoscope, 2010
Inhibitory leukocyte immunoglobulin-like receptors (LILRBs 1-5) transduce signals via intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that recruit protein tyrosine phosphatase ...non-receptor type 6 (PTPN6 or SHP-1), protein tyrosine phosphatase non-receptor type 11 (PTPN11 or SHP-2), or Src homology 2 domain-containing inositol phosphatase (SHIP), leading to negative regulation of immune cell activation. Certain of these receptors also play regulatory roles in neuronal activity and osteoclast development. The activation of LILRBs on immune cells by their ligands may contribute to immune evasion by tumors. Recent studies found that several members of LILRB family are expressed by tumor cells, notably hematopoietic cancer cells, and may directly regulate cancer development and relapse as well as the activity of cancer stem cells. LILRBs thus have dual concordant roles in tumor biology - as immune checkpoint molecules and as tumor-sustaining factors. Importantly, the study of knockout mice indicated that LILRBs do not affect hematopoiesis and normal development. Therefore LILRBs may represent ideal targets for tumor treatment. This review aims to summarize current knowledge on expression patterns, ligands, signaling, and functions of LILRB family members in the context of cancer development.
A novel inductor switching technique is used to design and implement a wideband LC voltage controlled oscillator (VCO) in 0.13 mum CMOS. The VCO has a tuning range of 87.2% between 3.3 and 8.4 GHz ...with phase noise ranging from -122 to -117.2 dBc/Hz at 1 MHz offset. The power varies between 6.5 and 15.4 mW over the tuning range. This results in a power-frequency-tuning normalized figure of merit (PFTN) between 6.6 and 10.2 dB which is one of the best reported to date.
: Multiplex autosomal short tandem repeat (STR) genotyping enables researchers to obtain genetic information from ancient human samples. In this study, we tested newly developed AmpFℓSTR® MiniFiler™ ...kit for autosomal STR analysis of ancient DNA (aDNA), using human femurs (n = 8) collected from medieval Korean tombs. After extracting aDNA from the bones, autosomal STR analyses were repeated for each sample using the AmpFℓSTR® MiniFiler™ and Identifiler™ kits. Whereas only 21.87% of larger‐sized loci profiles could be obtained with the Identifiler™ kit, 75% of the same loci profiles were determined by MiniFiler™ kit analysis. This very successful amplification of large‐sized STR markers from highly degraded aDNA suggests that the MiniFiler™ kit could be a useful complement to conventional STR kit analysis of ancient samples.
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