NFĸB Targeting in Bone Marrow Mesenchymal Stem Cell-Mediated Support of Age-Linked Hematological Malignancies.

Mesenchymal stem cells (MSCs) can become dysfunctional in patients with hematological disorders. An unanswered question is whether age-linked disruption of the bone marrow (BM) microenvironment is secondary to hematological dysfunction or vice versa. We therefore studied MSC function in patients with different hematological disorders and found decreased MHC-II except from one sample with acute myeloid leukemia (AML). The patients' MSCs were able to exert veto properties except for AML MSCs. While the expression of MHC-II appeared to be irrelevant to the immune licensing of MSCs, AML MSCs lost their ability to differentiate upon contact and rather, continued to proliferate, forming foci-like structures. We performed a retrospective study that indicated a significant increase in MSCs, based on phenotype, for patients with BM fibrosis. This suggests a role for MSCs in patients transitioning to leukemia. NFĸB was important to MSC function and was shown to be a potential target to sensitize leukemic CD34+/CD38- cells to azacitidine. This correlated with their lack of allogeneic stimulation. This study identified NFĸB as a potential target for combination therapy to treat leukemia stem cells and showed that understanding MSC biology and immune response could be key in determining how the aging BM might support leukemia. More importantly, we show how MSCs might be involved in transitioning the high risk patient with hematological disorder to AML.

IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells.

The switch of tumor cells from an epithelial to a mesenchymal-like phenotype [designated as epithelial-to-mesenchymal transition (EMT)] is known to induce tumor cell motility and invasiveness, therefore promoting metastasis of solid carcinomas. Although multiple studies have focused on elucidating the signaling events that initiate this phenotypic switch, there has been so far no characterization of the pattern of soluble mediators released by tumor cells undergoing EMT, and the potential impact that this phenotypic switch could have on the remodeling of the tumor microenvironment. Here we show that induction of EMT in human carcinoma cells via overexpression of the transcription factor Brachyury is associated with enhanced secretion of multiple cytokines, chemokines, and angiogenic factors and, in particular, with the induction of the IL-8/IL-8R axis. Our results also indicate the essential role of interleukin 8 (IL-8) signaling for the acquisition and/or maintenance of the mesenchymal and invasive features of Brachyury-overexpressing tumor cells and show that IL-8 secreted by tumor cells undergoing EMT could potentiate tumor progression by inducing adjacent epithelial tumor cells into EMT. Altogether, our results emphasize the potential role of EMT in the modulation of the tumor microenvironment via secretion of multiple soluble mediators and suggest that IL-8 signaling blockade may provide a means of targeting mesenchymal-like, invasive tumor cells.

Immunostimulatory effects of mesenchymal stem cell-derived neurons: implications for stem cell therapy in allogeneic transplantations.

Mesenchymal stem cells (MSCs) differentiate along various lineages to specialized mesodermal cells and also transdifferentiate into cells such as ectodermal neurons. MSCs are among the leading adult stem cells for application in regenerative medicine. Advantages include their immune-suppressive properties and reduced ethical concerns. MSCs also show immune-enhancing functions. Major histocompatibility complex II (MHC-II) is expected to be downregulated in MSCs during neurogenesis. Ideally, "off the shelf" MSCs would be suited for rapid delivery into patients. The question is whether these MSC-derived neurons can reexpress MHC-II in a milieu of inflammation. Western analyses demonstrated gradual decrease in MHC-II during neurogenesis, which correlated with the expression of nuclear CIITA, the master regulator of MHC-II expression. MHC-II expression was reversed by exogenous IFNY. One-way mixed lymphocyte reaction with partly differentiated neurons showed a stimulatory effect, which was partly explained by the release of the proinflammatory neurotransmitter substance P (SP), cytokines, and decreases in miR-130a and miR-206. The anti-inflammatory neurotransmitters VIP and CGRP were decreased at the peak time of immune stimulation. In summary, MSC-derived neurons show decreased MHC-II expression, which could be reexpressed by IFNY. The release of neurotransmitters could be involved in initiating inflammation, underscoring the relevance of immune responses as consideration for stem cell therapies.

Adult mesenchymal stem cells in neural regeneration and repair: Current advances and future prospects (Review).

Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine as they can be easily isolated from bone marrow (BM) aspirates and expanded in culture while maintaining their 'stemness'. In addition to differentiating into mesodermal cells, MSCs have shown considerable plasticity and generate ectodermal neurons and glia, which can be used to replace cells damaged by neurological diseases and injuries. These unique stem cells also exhibit immunomodulatory functions and secrete a variety of trophic factors which support regeneration and repair. This review focuses on the therapeutic usage of MSCs for neurodegenerative diseases and traumatic injuries to the nervous system. Animal studies demonstrate great promise for MSC transplantation in neurological disorders. In fact, a few clinical trials have already been initiated and show that MSCs are a safe cellular therapy and have great potential to become a viable treatment for neural disorders in the years to come.

Tachykinins and hematopoiesis.

Originally discovered in the 1930s, tachykinins have been a subject of renewed interest. Antagonists to the tachykinin receptors have shown potential in the treatment of a variety of maladies including neurodegenerative disorders, heart disease, pain perception and malignancies. Tachykinins have been the subject of intense studies due to their impact on hematopoiesis that has significant effects on endothelial tissue and vascular conditions. Hematopoiesis relies on a relatively small subset of bone marrow-resident hematopoietic stem cells. This review discusses the network developed by cytokines and the tachykinins to regulate hematopoiesis. An understanding of tachykinin effect on normal hematopoietic functions and their involvement in hematological disorders could lead to new treatments for bone marrow disorders such as fibrosis, leukemia and anemia.