Hal E. Broxmeyer

Bio: Hal E. Broxmeyer is an academic researcher from Indiana University. The author has contributed to research in topics: Stem cell & Bone marrow. The author has an hindex of 26, co-authored 56 publications receiving 11650 citations. Previous affiliations of Hal E. Broxmeyer include University of Texas Health Science Center at Houston & University of Washington.

Increased osteoclast development after estrogen loss: mediation by interleukin-6

Abstract: Osteoclasts, the cells that resorb bone, develop from hematopoietic precursors of the bone marrow under the control of factors produced in their microenvironment. The cytokine interleukin-6 can promote hematopoiesis and osteoclastogenesis. Interleukin-6 production by bone and marrow stromal cells is suppressed by 17 beta-estradiol in vitro. In mice, estrogen loss (ovariectomy) increased the number of colony-forming units for granulocytes and macrophages, enhanced osteoclast development in ex vivo cultures of marrow, and increased the number of osteoclasts in trabecular bone. These changes were prevented by 17 beta-estradiol or an antibody to interleukin-6. Thus, estrogen loss results in an interleukin-6-mediated stimulation of osteoclastogenesis, which suggests a mechanism for the increased bone resorption in postmenopausal osteoporosis.

Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells

Abstract: The purpose of this study was to evaluate human umbilical cord blood as an alternative to bone marrow in the provision of transplantable stem/progenitor cells for hematopoietic reconstitution Although no direct quantitative assay for human hematopoietic repopulating cells is at present available, the granulocyte-macrophage progenitor cell (CFU-GM) assay has been used with success as a valid indicator of engrafting capability We examined greater than 100 collections of human umbilical cord blood for their content of nucleated cells and granulocyte-macrophage, erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells, in many cases both before and after cryopreservation First it was determined that granulocyte-macrophage, erythroid, and multipotential progenitor cells remained functionally viable in cord blood untreated except for addition of anticoagulant for at least 3 days at 4 degrees C or 25 degrees C (room temperature), though not at 37 degrees C, implying that these cells could be satisfactorily studied and used or cryopreserved for therapy after transport of cord blood by overnight air freight carriage from a remote obstetrical service Granulocyte-macrophage progenitor cells from cord blood so received responded normally to stimulation by purified recombinant preparations of granulocyte-macrophage, granulocyte, and macrophage colony-stimulating factors and interleukin 3 The salient finding, based on analysis of 101 cord blood collections, is that the numbers of progenitor cells present in the low-density (less than 1077 gm/ml) fraction after Ficoll/Hypaque separation typically fell within the range that has been reported for successful engraftment by bone marrow cells Another observation of practical importance is that procedures to remove erythrocytes or granulocytes prior to freezing, and washing of thawed cells before plating, entailed large losses of progenitor cells, the yield of unwashed progenitor cells from unfractionated cord blood being many times greater The provisional inference is that human umbilical cord blood from a single individual is typically a sufficient source of cells for autologous (syngeneic) and for major histocompatibility complex-matched allogeneic hematopoietic reconstitution

Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist

Abstract: Improving approaches for hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is clinically important because increased numbers of these cells are needed for enhanced transplantation. Chemokine stromal cell derived factor-1 (also known as CXCL12) is believed to be involved in retention of HSCs and HPCs in bone marrow. AMD3100, a selective antagonist of CXCL12 that binds to its receptor, CXCR4, was evaluated in murine and human systems for mobilizing capacity, alone and in combination with granulocyte colony-stimulating factor (G-CSF). AMD3100 induced rapid mobilization of mouse and human HPCs and synergistically augmented G-CSF–induced mobilization of HPCs. AMD3100 also mobilized murine long-term repopulating (LTR) cells that engrafted primary and secondary lethally-irradiated mice, and human CD34+ cells that can repopulate nonobese diabetic-severe combined immunodeficiency (SCID) mice. AMD3100 synergized with G-CSF to mobilize murine LTR cells and human SCID repopulating cells (SRCs). Human CD34+ cells isolated after treatment with G-CSF plus AMD3100 expressed a phenotype that was characteristic of highly engrafting mouse HSCs. Synergy of AMD3100 and G-CSF in mobilization was due to enhanced numbers and perhaps other characteristics of the mobilized cells. These results support the hypothesis that the CXCL12-CXCR4 axis is involved in marrow retention of HSCs and HPCs, and demonstrate the clinical potential of AMD3100 for HSC mobilization.

Human Adipose Tissue Is a Source of Multipotent Stem Cells

Abstract: Much of the work conducted on adult stem cells has focused on mesenchymal stem cells (MSCs) found within the bone marrow stroma. Adipose tissue, like bone marrow, is derived from the embryonic mesenchyme and contains a stroma that is easily isolated. Preliminary studies have recently identified a putative stem cell population within the adipose stromal compartment. This cell population, termed processed lipoaspirate (PLA) cells, can be isolated from human lipoaspirates and, like MSCs, differentiate toward the osteogenic, adipogenic, myogenic, and chondrogenic lineages. To confirm whether adipose tissue contains stem cells, the PLA population and multiple clonal isolates were analyzed using several molecular and biochemical approaches. PLA cells expressed multiple CD marker antigens similar to those observed on MSCs. Mesodermal lineage induction of PLA cells and clones resulted in the expression of multiple lineage-specific genes and proteins. Furthermore, biochemical analysis also confirmed lineage-specific activity. In addition to mesodermal capacity, PLA cells and clones differentiated into putative neurogenic cells, exhibiting a neuronal-like morphology and expressing several proteins consistent with the neuronal phenotype. Finally, PLA cells exhibited unique characteristics distinct from those seen in MSCs, including differences in CD marker profile and gene expression.

Alternative activation of macrophages

Abstract: The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.

Mesenchymal Stem Cells

Abstract: Institute of Biological Medicine, Moscow The formation of the concept of a mesenchymal stem cell (MSC) is a priority of Russian biological science. A. Ya. Fridenshtein and his colleagues were the first who experimentally proved the existence of MSC. Osteogenic potential of fibroblastlike bone marrow cells of different mammalian species was demonstrated [25,26]. Fibroblast-like bone marrow cells often formed discrete adhesive colonies in vitro [27,28,47]. After heteroand orthotopic transplantation in vivo cloned cells from these colonies formed bone, cartilaginous, fibrous, and adipose tissues [48]. Intensive self-renewal and multipotency of fibroblast-like colony-forming cells from the bone marrow allowed Fridenshtein and Owen to formulate a concept of multipotent mesenchymal precursor cells (MPC) [62]. An ordered chain of finely regulated cell proliferation, migration, differentiation, and maturation processes underlies the formation of the majority of cell lineages in adult organisms. The earliest cell elements in this chain are stem cells (SC). Along with extensive self-renewal capacity, SC possess a great differentiation potential. Apart from well studied hemopoietic and intestinal SC, other SC classes were recently discovered in adult organism. Until recently it was considered that SC in adults can give rise to cell lines specific to tissues where these cells are located; however, new facts necessitated revision of this concept. Hemopoietic SC capable of differentiating into all cell elements of the blood, can also be a source of hepatic oval cells [65]; neural SC, precursors of neurons and glia [2,3], serve as the source of early and committed hemopoietic precursors [10]. MSC, a source of bone, cartilaginous, and adipose tissue cells, can differentiate into neural cells [46]. Tissue growth and reparation are associated with migration of uncommitted precursor cells from other tissues. During muscle tissue reparation mesenchymal SC migrate from the bone marrow into skeletal muscles [24]. Hence, in addition to capacity to unlimited division and reproduction of a wide spectrum of descendants of a certain differentiation line, adult SC are characterized by high plasticity. The existence of a rare type of somatic pluripotent SC, common precursors of all SC in an adult organism, is hypothesized [79]. Another important characteristic of SC is their migration from the tissue niche into circulation, which was experimentally proven for hemopoietic and MSC [69,73]. For activation of the differentiation program, circulating SC should get into an appropriate microenvironment [75,78]. A potent stimulus for investigation of SC is the possibility of their clinical use in cell and gene therapy. The bone marrow contains multipotent MSC, which can be easily isolated and cultured in vitro. It is therefore interesting to analyze some fundamental aspects of MSC biology and the possibilities of their clinical use. MSC descendants are involved in the formation of bones, cartilages, tendons, adipose and muscle tissues, and stroma maintaining the hemopoiesis [12,19,51]. The term MPC is used to denote MSC and their committed descendants capable of differentiating into at least two types of mature cells, which are present in the bone marrow and some mesenchymal tissues [16,19,57,82].

Cellular and molecular mechanisms of fibrosis.

Abstract: Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.