Project description:The activity of bone marrow hematopoeitic cells is tightly controlled by neurogenic innervations. As bone marrow cells mainly receive innervation from beta-3 adrenergic receptor, here we investigated the impact of beta3-adrenergic innervation on bone marrow cell transcriptome alterations. We sorted hematopoetic stem cells (HSCs) from wild type mice (control group) or Adrb3-/- mice (devoid of beta3-adrenergic receptor). Thereafter, Nanostring assessment was performed to compare the transcriptome alterations.
Project description:Aging of hematopoietic stem cells (HSCs) is associated with the decline of their regenerative capacity, and multi-lineage differentiation potential, contributing to development of blood disorders. The bone marrow microenvironment was recently suggested to influence HSC aging, however the underlying mechanisms remain largely unknown. Here, we show that HSC aging critically depends on bone marrow innervation by the sympathetic nervous system (SNS), as premature loss of SNS nerves or adrenoreceptor b3 (ADRb3) signaling in the microenvironment accelerated the appearance of HSC aging phenotypes reminiscent of physiological aging. Strikingly, supplementation of ADRb3 sympathomimetics to old mice significantly rejuvenated in vivo function of old HSCs, suggesting that the preservation or restitution of SNS innervation during aging may hold the potential for novel HSC rejuvenation strategies.
Project description:In this study, we aimed to study the effect of Beta-2 Adrenergic Receptor stimulation on secreted proteins in triple negative breast cancer cell lines. We also wanted to compare protein expression in parental or bone tropic metastatic cell lines and how they respond to adrenergic signaling.
Project description:BACKGROUND Enteric glia contribute to the pathophysiology of various intestinal immune-driven diseases, such as postoperative ileus (POI), a motility disorder and common complication after abdominal surgery. Enteric gliosis of the intestinal muscularis externa (ME) has been identified as part of POI development. However, the glia-restricted responses and activation mechanisms are poorly understood. The sympathetic nervous system becomes rapidly activated by abdominal surgery. It modulates intestinal immunity, innervates all intestinal layers, and directly interfaces with enteric glia. We hypothesized that sympathetic innervation controls enteric glia reactivity in response to surgical trauma. METHODS Sox10iCreERT2/Rpl22HA/+ mice were subjected to a mouse model of laparotomy or intestinal manipulation to induce POI. Histological, protein, and transcriptomic analyses were performed to analyze glia-specific responses. Interactions between the sympathetic nervous system and enteric glia were studied in mice chemically depleted of TH+ sympathetic neurons and glial-restricted Sox10iCreERT2/JellyOPfl/+/Rpl22HA/+ mice, allowing optogenetic stimulation of β-adrenergic downstream signaling and glial-specific transcriptome analyses. A laparotomy model was used to study the effect of sympathetic signaling on enteric glia in the absence of intestinal manipulation. Mechanistic studies included adrenergic receptor expression profiling in vivo and in vitro and adrenergic agonism treatments of primary enteric glial cell cultures to elucidate the role of sympathetic signaling in acute enteric gliosis and POI. RESULTS With ~4000 differentially expressed genes, the most substantial enteric glia response occurs early after intestinal manipulation. During POI, enteric glia switch into a reactive state and continuously shape their microenvironment by releasing inflammatory and migratory factors. Sympathetic denervation reduced the inflammatory response of enteric glia in the early postoperative phase. Optogenetic and pharmacological stimulation of β-adrenergic downstream signaling triggered enteric glia reactivity. Finally, distinct adrenergic agonists revealed β-1/2 adrenoceptors as the molecular targets of sympathetic–driven enteric glial reactivity. CONCLUSIONS Enteric glia act as early responders during post-traumatic intestinal injury and inflammation. Intact sympathetic innervation and active β-adrenergic receptor signaling in enteric glia is a trigger of the immediate glial postoperative inflammatory response. With immune-activating cues originating from the sympathetic nervous system as early as the initial surgical incision, adrenergic signaling in enteric glia presents a promising target for preventing POI development.
Project description:RATIONALE: Radiation therapy uses high-energy x-rays to damage cancer cells. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.
PURPOSE: Phase II trial to study the effectiveness of bone marrow transplantation in treating patients who have hematologic cancer.
Project description:Transcriptomic analysis of the temporal changes induced in mouse bone marrow derived macrophages (BMDMs) by the cytokine Interferon-beta over a timecourse of 0 to 24 hours of treatment. We set out to study the transcriptional events in mouse macrophages over time following stimulation with Interferon-beta. Mouse bone marrow derived macrophages were stimulated for 1, 2, 4, 8 and 24 hours with 10U/mL mouse interferon-beta or left untreated.
Project description:Maturation of hematopoietic stem and progenitor cells (HSPC) in bone marrow (BM) and of T-lymphocytes in thymus occurs within stromal areas innervated by adrenergic fibers of the sympathetic nervous system (SNS). Here we have discovered that in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), SNS signaling to specific stromal cells expressing beta 3 adrenergic receptors (B3AR) promote differentiation and mobilization of hematopoietic precursors in BM and generation of regulatory T-lymphocytes (Treg) in the thymus. We demonstrate that the functionality of B3AR on BM and thymic stromal cells is under control of hypothalamic neurons expressing Agouti-Related Protein (AgRP), which are activated in EAE. The finding that AgRP neuropeptide is increased in the serum of people with MS, supports that AgRP neurons might be activated also in MS.
Project description:Eight weeks old male Adrb1tm1BkkAdrb2tm1Bkk/J , stock number 003810, were purchased from The Jackson Laboratory. These mice are homozygous null for the Adrb1 and Adrb2 genes, and are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Mice were euthanized, and the whole bone marrow was extracted using established methods.1 Whole bone marrow cells from Adrb1tm1BkkAdrb2tm1Bkk/J mice were reconstituted into lethally- irradiated (950 Rad) C57BL/6J mice using a single retro-orbital injection at a ratio of 1:4 (Adrb1tm1BkkAdrb2tm1Bkk/J to C57BL/6J). All reconstituted mice were recovered for 2-3 months prior to tissue collection for mRNA arrays (1) The FASEB Journal 2015:29(1),652.13. Eight control animals and eight animals that received new bone marrow from double adrenergic receptor knockout (treated KO chimera). Following recovery, tissues that were harvested included bone marrow, brain, and distal colon.