Carbon Monoxide Activates PERK-Regulated Autophagy to Induce Immunometabolic Reprogramming and Boost Antitumor T-cell Function.

Unlabelled: Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells' fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost antitumor T-cell function by targeting ER-mitochondria cross-talk have not yet been exploited.

Hematopoietic stem cell-derived functional osteoblasts exhibit therapeutic efficacy in a murine model of osteogenesis imperfecta.

Currently, there is no cure for osteogenesis imperfecta (OI)-a debilitating pediatric skeletal dysplasia. Herein we show that hematopoietic stem cell (HSC) therapy holds promise in treating OI. Using single-cell HSC transplantation in lethally irradiated oim/oim mice, we demonstrate significant improvements in bone morphometric, mechanics, and turnover parameters.

Pro-Survival Lipid Sphingosine-1-Phosphate Metabolically Programs T Cells to Limit Anti-tumor Activity.

Sphingosine 1-phosphate (S1P), a bioactive lysophospholipid generated by sphingosine kinase 1 (SphK1), regulates lymphocyte egress into circulation via S1P receptor 1 (S1PR1) signaling, and it controls the differentiation of regulatory T cells (Tregs) and T helper-17 cells. However, the mechanisms by which receptor-independent SphK1-mediated intracellular S1P levels modulate T cell functionality remains unknown. We show here that SphK1-deficient T cells maintain central memory phenotype and exhibit higher mitochondrial respiration and reduced differentiation to Tregs.

Hematopoietic Stem Cells as a Novel Source of Dental Tissue Cells.

While earlier studies have suggested that cells positive for hematopoietic markers can be found in dental tissues, it has yet to be confirmed. To conclusively demonstrate this, we utilized a unique transgenic model in which all hematopoietic cells are green fluorescent protein (GFP). Pulp, periodontal ligament (PDL) and alveolar bone (AvB) cell culture analysis demonstrated numerous GFP cells, which were also CD45 (indicating hematopoietic origin) and co-expressed markers of cellular populations in pulp (dentin matrix protein-1, dentin sialophosphoprotein, alpha smooth muscle actin [ASMA], osteocalcin), in PDL (periostin, ASMA, vimentin, osteocalcin) and in AvB (Runx-2, bone sialoprotein, alkaline phosphatase, osteocalcin).

CD38-NADAxis Regulates Immunotherapeutic Anti-Tumor T Cell Response.

Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD-dependent activity of the histone deacetylase Sirt1.

Plasticity of hematopoietic stem cells.

Almost two decades ago, a number of cell culture and preclinical transplantation studies suggested the striking concept of the tissue-reconstituting ability of hematopoietic stem cells (HSCs). While this heralded an exciting time of radically new therapies for disorders of many organs and tissues, the concept was soon mired by controversy and remained dormant. This chapter provides a brief review of evidence for HSC plasticity including our findings based on single HSC transplantation in mouse.

Hematopoietic Origin of Murine Lung Fibroblasts.

Multiple origins, including the bone marrow, have been suggested to contribute to fibroblast populations in the lung. Using bone marrow reconstitution strategies, the present study tested the hypothesis that the bone marrow hematopoietic stem cell (HSC) gives rise to lung tissue fibroblasts in vivo. Data demonstrate that the nonadherent bone marrow fraction is enriched for CD45(+) HSC-derived cells and was able to reconstitute hematopoiesis in lethally irradiated animals.

Hematopoietic stem cell-derived adipocytes and fibroblasts in the tumor microenvironment.

The tumor microenvironment (TME) is complex and constantly evolving. This is due, in part, to the crosstalk between tumor cells and the multiple cell types that comprise the TME, which results in a heterogeneous population of tumor cells and TME cells. This review will focus on two stromal cell types, the cancer-associated adipocyte (CAA) and the cancer-associated fibroblast (CAF).

Hematopoietic stem cells are pluripotent and not just "hematopoietic".

Over a decade ago, several preclinical transplantation studies suggested the striking concept of the tissue-reconstituting ability (often referred to as HSC plasticity) of hematopoietic stem cells (HSCs). While this heralded an exciting time of radically new therapies for disorders of many organs and tissues, the concept was soon mired in controversy and remained dormant for almost a decade. This commentary provides a concise review of evidence for HSC plasticity, including more recent findings based on single HSC transplantation in mouse and clinical transplantation studies.

Hematopoietic stem cells give rise to osteo-chondrogenic cells.

Repair of bone fracture requires recruitment and proliferation of stem cells with the capacity to differentiate to functional osteoblasts. Given the close association of bone and bone marrow (BM), it has been suggested that BM may serve as a source of these progenitors. To test the ability of hematopoietic stem cells (HSCs) to give rise to osteo-chondrogenic cells, we used a single HSC transplantation paradigm in uninjured bone and in conjunction with a tibial fracture model.

Amelioration of a mouse model of osteogenesis imperfecta with hematopoietic stem cell transplantation: microcomputed tomography studies.

Objective: To test the hypothesis that hematopoietic stem cells (HSCs) generate bone cells using bone marrow (BM) cell transplantation in a mouse model of osteogenesis imperfecta (OI). OI is a genetic disorder resulting from abnormal amount and/or structure of type I collagen and is characterized by osteopenia, fragile bones, and skeletal deformities. Homozygous OI murine mice (oim; B6C3Fe a/a-Col1a2(oim)/J) offer excellent recipients for transplantation of normal HSCs, because fast turnover of osteoprogenitors has been shown.

MCP1 directs trafficking of hematopoietic stem cell-derived fibroblast precursors in solid tumor.

Our previous studies have demonstrated that hematopoietic stem cells (HSCs) are a novel source of carcinoma-associated fibroblasts. However, the mechanisms regulating recruitment and homing of HSC-derived carcinoma-associated fibroblasts or their precursors to the tumor microenvironment are unknown. Herein, we demonstrate using a single cell transplantation model that circulating fibroblast precursors (CFPs) are of HSC origin.

Hematopoietic stem cell origin of human fibroblasts: cell culture studies of female recipients of gender-mismatched stem cell transplantation and patients with chronic myelogenous leukemia.

Objective: Our series of studies using transplantation of single hematopoietic stem cells (HSCs) demonstrated that mouse fibroblasts/myofibroblasts are derived from HSCs. In order to determine the origin of human fibroblasts, we established a method for culturing fibroblasts from human peripheral blood (PB) mononuclear cells and studied fibroblasts from gender-mismatched HSC transplant recipients and patients with untreated Philadelphia chromosome-positive chronic myelogenous leukemia (CML).

Materials And Methods: We cultured PB cells from three female subjects who showed near-complete hematopoietic reconstitution from transplantation of granulocyte-colony stimulating factor-mobilized male PB cells and examined the resulting fibroblasts using fluorescent in situ hybridization for Y chromosome.

Inhibition of superoxide generation upon T-cell receptor engagement rescues Mart-1(27-35)-reactive T cells from activation-induced cell death.

Cytotoxic T lymphocytes (CTL) may undergo massive expansion upon appropriate antigenic stimulation. Homeostasis is maintained by a subsequent "contraction" of these cells. Activation-induced cell death (AICD) and programmed cell death prevent the untoward side effects, arising from excessive numbers and prolonged persistence of activated CTL, that occur upon uncontrolled and/or continued expansion.

Hematopoietic stem cell origin of adipocytes.

Objective: It has generally been believed that adipocytes are derived from mesenchymal stem cells via fibroblasts. We recently reported that fibroblasts/myofibroblasts in a number of tissues and organs are derived from hematopoietic stem cells (HSCs). In the present study, we tested the hypothesis that HSCs also give rise to adipocytes.

Overexpression of COX-2 in human osteosarcoma cells decreases proliferation and increases apoptosis.

Overexpression of cyclooxygenase-2 (COX-2) is generally considered to promote tumorigenesis. To investigate a potential role of COX-2 in osteosarcoma, we overexpressed COX-2 in human osteosarcoma cells. Saos-2 cells deficient in COX-2 expression were retrovirally transduced or stably transfected with murine COX-2 cDNA.

Fluid flow induces Rankl expression in primary murine calvarial osteoblasts.

Mechanical loading of bone generates fluid flow within the mineralized matrix that exerts fluid shear stress (FSS) on cells. We examined effects of FSS on receptor activator of nuclear factor kappa B ligand (RANKL), a critical factor for osteoclast formation. Primary murine osteoblasts were subjected to pulsatile FSS (5 Hz, 10 dynes/cm(2)) for 1 h and then returned to static culture for varying times (post-FSS).

Calcium deficiency-induced secondary hyperparathyroidism and osteopenia are rapidly reversible with calcium supplementation in growing rabbit pups.

The reversibility of osteopenia secondary to isolated Ca deficiency (CaDef) is still not clear. We studied the effect of severe CaDef on Ca homeostasis and bone accrual in a 'hypercalcaemic' animal, the rabbit, during the post-weaning period and its reversibility on Ca supplementation. Male Belgian 5-week-old rabbit pups were fed CaDef diet (0.

Role of Cbfa1/Runx2 in the fluid shear stress induction of COX-2 in osteoblasts.

Induction of cyclooxygenase-2 (COX-2) is thought to be important for the anabolic effects of mechanical loading. The transcription factor Cbfa1/Runx2 is essential for osteoblastic differentiation. We examined the role of Cbfa1 in the fluid shear stress (FSS) induction of COX-2 in MC3T3-E1 cells stably transfected with a COX-2 promoter-luciferase reporter.

Differential regulation of platelet-derived growth factor stimulated migration and proliferation in osteoblastic cells.

Osteoblastic migration and proliferation in response to growth factors are essential for skeletal development, bone remodeling, and fracture repair, as well as pathologic processes, such as metastasis. We studied migration in response to platelet-derived growth factor (PDGF, 10 ng/ml) in a wounding model. PDGF stimulated a twofold increase in migration of osteoblastic MC3T3-E1 cells and murine calvarial osteoblasts over 24-48 h.