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Description:
Hematopoietic stem cells (HSCs) undergo carefully-orchestrated, dynamic processes of specification, self-renewal and differentiation to yield the most abundant cells in the body. Approximately 1015 cells of diverse structure and function are generated from vastly smaller pools of HSCs over the average human lifespan, in a manner highly responsive to developmental and environmental cues. Cell-autonomous functions define HSCs, from classical experimental systems to clinical hematopoietic cell transplantation. As a consequence, HSC-intrinsic factors, such as epigenetic programs, transcription factors, and growth factor signaling pathways, dominate oft-cited models of hematopoiesis. A fuller understanding of the life of HSCs is revealed through the lens of basic stem cell biology, incorporating determinants such as niche contacts, morphogen gradients, physical forces, and changes in these over time. This session will present the latest developments in our understanding of extrinsic factors that regulate HSC development and function in vertebrate systems, from early specification to homeostasis, regeneration and aging.
Dr. Trista North will discuss the role of the extrinsic factors in governing the location, onset and progression of HSC formation in the vertebrate embryo. Following earlier waves of production of lineage restricted progenitors, HSCs develop de novo from the hemogenic endothelium in the embryonic dorsal aorta, via a process termed endothelial to hematopoietic transition. While key transcriptional regulators of hemogenic endothelial specification and HSC formation are well established in the field, it is only more recently appreciated how these pathways are activated to initiate commitment to HSC production, and repress endothelial fate. In particular, extrinsic regulation from the developing embryo appears to play a key role in biomechanical and metabolic stimuli, inflammatory signals, and morphogen gradients converge to coordinately regulate the timing and location of HSC production. Dr. North will outline emerging data describing the integration of extrinsic developmental cues with intracellular signaling networks to regulate the onset and maintenance of HSC formation across vertebrate species, from zebrafish to human.
Dr. John Chute will discuss extrinsic factors that regulate adult HSC homeostasis. Bone marrow endothelial cells (BMECs) have an essential role in regulating HSC regeneration following myelotoxicity, but the mechanisms through which BMECs regulate HSC regeneration are not well understood. Dr. Chute will describe the discovery that semaphorin 3A (SEMA3A) - NRP1 signaling negatively regulates BMEC regeneration following chemotherapy or total body irradiation. Systemic administration of a blocking anti-NRP1 antibody or EC-specific deletion of NRP1 or SEMA3A causes the rapid regeneration of the BM vasculature and the hematopoietic system in irradiated mice. Regenerating BMECs in anti-NRP1-treated mice display significantly increased expression and secretion of R-spondin 2, a Wnt pathway amplifying protein, compared to control BMECs. BM HSCs concordantly upregulate expression of LGR5, a receptor for R-spondin 2. Systemic administration of anti-R-spondin 2 antibody blocks both HSC regeneration and hematologic recovery in irradiated mice that otherwise occurred in response to anti-NRP1 treatment. These studies suggest that BMECs drive hematopoietic regeneration through secretion of R-spondin 2 and activation of LGR5+ HSCs.
Dr. Laura Calvi will discuss characteristics of HSC aging in murine models and in humans. These characteristics have been in part ascribed to cell-autonomous processes, but, given the regulatory interactions with HSC with their niche, the aged microenvironment would also be expected to contribute. Recent data from multiple laboratories have outlined mechanisms by which the aged microenvironment influences hematopoietic stem cells, providing evidence the aged components of the microenvironment. Dr. Calvi will review this work and focus particularly on cellular constituents found to impact HSC skewing, as shown by in vivo models. These will include data on aged multipotent stromal cells as well as macrophages.
Dr. Trista North will discuss the role of the extrinsic factors in governing the location, onset and progression of HSC formation in the vertebrate embryo. Following earlier waves of production of lineage restricted progenitors, HSCs develop de novo from the hemogenic endothelium in the embryonic dorsal aorta, via a process termed endothelial to hematopoietic transition. While key transcriptional regulators of hemogenic endothelial specification and HSC formation are well established in the field, it is only more recently appreciated how these pathways are activated to initiate commitment to HSC production, and repress endothelial fate. In particular, extrinsic regulation from the developing embryo appears to play a key role in biomechanical and metabolic stimuli, inflammatory signals, and morphogen gradients converge to coordinately regulate the timing and location of HSC production. Dr. North will outline emerging data describing the integration of extrinsic developmental cues with intracellular signaling networks to regulate the onset and maintenance of HSC formation across vertebrate species, from zebrafish to human.
Dr. John Chute will discuss extrinsic factors that regulate adult HSC homeostasis. Bone marrow endothelial cells (BMECs) have an essential role in regulating HSC regeneration following myelotoxicity, but the mechanisms through which BMECs regulate HSC regeneration are not well understood. Dr. Chute will describe the discovery that semaphorin 3A (SEMA3A) - NRP1 signaling negatively regulates BMEC regeneration following chemotherapy or total body irradiation. Systemic administration of a blocking anti-NRP1 antibody or EC-specific deletion of NRP1 or SEMA3A causes the rapid regeneration of the BM vasculature and the hematopoietic system in irradiated mice. Regenerating BMECs in anti-NRP1-treated mice display significantly increased expression and secretion of R-spondin 2, a Wnt pathway amplifying protein, compared to control BMECs. BM HSCs concordantly upregulate expression of LGR5, a receptor for R-spondin 2. Systemic administration of anti-R-spondin 2 antibody blocks both HSC regeneration and hematologic recovery in irradiated mice that otherwise occurred in response to anti-NRP1 treatment. These studies suggest that BMECs drive hematopoietic regeneration through secretion of R-spondin 2 and activation of LGR5+ HSCs.
Dr. Laura Calvi will discuss characteristics of HSC aging in murine models and in humans. These characteristics have been in part ascribed to cell-autonomous processes, but, given the regulatory interactions with HSC with their niche, the aged microenvironment would also be expected to contribute. Recent data from multiple laboratories have outlined mechanisms by which the aged microenvironment influences hematopoietic stem cells, providing evidence the aged components of the microenvironment. Dr. Calvi will review this work and focus particularly on cellular constituents found to impact HSC skewing, as shown by in vivo models. These will include data on aged multipotent stromal cells as well as macrophages.