HSC Niche Biology and HSC Expansion Ex Vivo

HSC niches have been defined in more detail with respect to their cellular composition over the past few years. Molecular characterization of these niches has been successfully initiated. Molecular pathways that govern the mode of division of HSCs are being discovered. HSC intrinsic mechanisms, such as metabolic pathways regulating HSC self-renewal, can be modulated by the environment and/or niche factors. High-throughput screening of chemical compound libraries has resulted in a few successful attempts towards HSC expansion ex vivo. Attempts to engineer stem cell niches ex vivo in 3D matrix culture systems are promising. Hematopoietic stem cell (HSC) transplantation can restore a new functional hematopoietic system in recipients in cases where the system of the recipient is not functional or for example is leukemic. However, the number of available donor HSCs is often too low for successful transplantation. Expansion of HSCs and thus HSC self-renewal ex vivo would greatly improve transplantation therapy in the clinic. In vivo, HSCs expand significantly in the niche, but establishing protocols that result in HSC expansion ex vivo remains challenging. In this review we discuss current knowledge of niche biology, the intrinsic regulators of HSC self-renewal in vivo, and introduce novel niche-informed strategies of HSC expansion ex vivo. Hematopoietic stem cell (HSC) transplantation can restore a new functional hematopoietic system in recipients in cases where the system of the recipient is not functional or for example is leukemic. However, the number of available donor HSCs is often too low for successful transplantation. Expansion of HSCs and thus HSC self-renewal ex vivo would greatly improve transplantation therapy in the clinic. In vivo, HSCs expand significantly in the niche, but establishing protocols that result in HSC expansion ex vivo remains challenging. In this review we discuss current knowledge of niche biology, the intrinsic regulators of HSC self-renewal in vivo, and introduce novel niche-informed strategies of HSC expansion ex vivo. stem cells from an HLA-matched donor are transplanted. leads to the generation of two cells with different potential: a daughter stem cell and a daughter progenitor cell. ATM regulates reprogramming efficiency and genomic stability; Atm−/− mice exhibit pancytopenia, bone marrow (BM) failure, and hematopoietic stem cell (HSC) exhaustion. an individual’s own stem cells are collected in advance and transplanted to herself/himself after chemotherapy or radiation therapy. process that degrades/destructs dysfunctional components of the cytoplasm (autophagy) or dysfunctional mitochondria (mitophagy) in lysosomes. human cells expressing CD34; include both stem and progenitor cell populations. a property of cells that is governed/regulated by signaling/factors within, but not through, the niche environment. transplantation of donor HSCs or BM cells in the presence of genetically trackable congenic competitor BM cells. the generation of progenitor cells from stem cells; necessary to produce mature blood cells. HSC niche in close association to a bone surface. includes among other elements collagen, fibronectin, dystroglycan, heparin sulfate, proteoglycans, osteopontin, and laminins. a subset of endothelial cells with the potential to differentiate into hematopoietic cells. the process of blood cell formation from HSCs. a state of turnover in which the cells are ‘used up’; HSCs can undergo exhaustion due to the high demand of reconstitution in stress or serial transplant settings. the process of increasing the number of HSCs. a specific BM environment that provides cellular, chemical, and molecular constituents and contributes to the regulation of HSC survival, self-renewal, and differentiation. a procedure to replenish the blood system of a recipient by providing a sufficient number of new HSCs cells from a donor. encodes the major histocompatibility complex (MHC) proteins in humans and functions as a determinant of transplant rejection. intravenously injected HSCs from a donor into a recipient to reconstitute the hematopoietic system. a distinct fraction of murine hematopoietic stem and progenitor cells in the BM; these are characterized as Lin−Sca-1+c-Kit+ based on surface marker expression. give rise to multilineage engraftment post-transplantation for a timeframe of at least 20 weeks. LT-HSCs are phenotypically characterized as Lin−IL-7α−Sca-1+c-Kit+Flt3−CD34−CD150+CD48− cells. primitive hematopoietic cells capable of initiating and sustaining in vitro cultures for >5 weeks, including colony-forming cells (CFCs) or cobblestone area forming cells. controls nutrient sensing, metabolism, and mitogenic signals to regulate cell quiescence, proliferation, cell survival, and longevity; important for PI3K, Akt, and insulin signal-transduction pathways. see autophagy. nonobese diabetic (NOD)-severe combined immunodeficiency (SCID) mice display impaired T and B cell lymphocytes and deficient natural killer (NK) cell function. They can accept allogeneic and xenogeneic grafts, and are thus an excellent model system to study human cell transplantation and engraftment (xenotransplants). reduction in the number of all three blood cell types: red blood cells, white blood cells, and platelets. a nontoxic exogenous 2-nitroimidazole low molecular weight compound that forms adducts with thiol groups in hypoxic environments and works as an effective and nontoxic hypoxia marker. the state of being inactive or dormant in the cell division cycle. the capacity to confer long-term survival after lethal irradiation (e.g., mice). regarded as the gold standard assay to determine HSC function in vivo. Serial (multiple, consecutive, up to 6) transplantations (e.g., in mice) test the ability of HSCs to undergo self-renewal in vivo. human HSCs capable of long-term reconstitution in immunodeficient mice (xenotransplant approach). cell division producing two daughter stem cells. small blood vessel capillaries of irregular tubular space for blood passage within the BM. HSCs can reside near the sinusoid networks that present a sinusoidal niche. leads to the generation of two similar types of daughter cells: either two stem or two progenitor cells. well-established assay to measure multilineage reconstitution and self-renewal potential of hematopoietic stem and progenitor cells in irradiated recipient mice in vivo. a transplantation setting in which the donor of a tissue graft or organ transplant is of a species different from that of the recipient, for example human stem cell transplantation into mice. Generally, immunodeficient mice, in other words SCID, NOD/SCID, or NOD/SCID/Ycnull (NSG) mice, are used as recipients in human–mouse xenograft models.