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Stress Can Be a Good Thing for Blood Formation
Cell Stem Cell
Previews Stress Can Be a Good Thing for Blood Formation Nancy A. Speck1,* 1Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2016.08.011
Like politics, most developmental signals are local. However, in this issue of Cell Stem Cell, Kwan et al. (2016) and colleagues describe how a stress-induced signal that originates in the zebrafish brain promotes the formation of blood at a distant site, the dorsal aorta. Multiple signaling pathways are required to produce blood cells in the embryo, including the Notch, Wnt, Hedgehog, bone morphogenic protein (BMP), and fibroblast growth factor pathways (Clements and Traver, 2013). These signals are generally delivered locally, for example on the plasma membrane of adjacent cells (Notch), or are secreted and diffuse over modest distances (Wnt, BMP, and Hedgehog). However, some signals travel long distances through the circulation to regulate blood cell formation. In this issue of Cell Stem Cell, Kwan et al., (2016) report that a pathway activated by stress in the brain promotes hematopoietic stem and progenitor cell (HSPC) formation at a distance in the dorsal aorta of zebrafish embryos. An important site of blood formation in the embryo, particularly for the development of hematopoietic stem cells, is the dorsal aorta, which contains a transient population of blood-producing endothelial cells called hemogenic endothelium (Tober et al., 2016). At approximately embryonic days 10.5–11.5 in the mouse, embryonic days 27–40 in the human, and 30–54 hr post-fertilization in zebrafish embryos, hemogenic endothelial cells undergo an endothelial to hematopoietic transition (EHT), similar to the more well-known epithelial to mesenchymal transition (EMT), and become HSPCs. The HSPCs then enter the circulation and colonize the fetal liver, and later the bone marrow, in mouse and human embryos. The transcription factor Runx1 is expressed in the hemogenic endothelium and is required for the EHT (Tober et al., 2016). By monitoring the expression of Runx1, and also that of the transcription factor Myb, which is expressed shortly after Runx1 in HSPCs, various groups have identified small molecules, genes,
or physical processes that enhance or inhibit HSPC formation (Adamo et al., 2009; Burns et al., 2009; North et al., 2007, 2009). The zebrafish embryo is particularly well suited for these types of analyses for multiple reasons, one of which is that signals that normally originate from a distant site in the embryo can be identified. A previous chemical genetic screen of small molecules using zebrafish embryos identified neuroregulators that could increase Runx1 and Myb expression and HSPC formation in the dorsal aorta (North et al., 2007). In this issue, Kwan et al. (2016) determine the mechanism by which one of these regulators, serotonin, enhances HSPC formation. Serotonin is a monoamine derived from tryptophan. The vast majority of serotonin in the zebrafish embryo is produced in the periphery (skin, gut, and pineal gland), where it regulates many physiological functions including gut motility, cardiac function, and platelet aggregation. Serotonin is also produced in the brain, where it functions as a neurotransmitter that regulates mood, appetite, sleep, and stress. Intuitively, one would expect that peripheral serotonin would be the most important regulator of HSPC formation in the dorsal aorta since it is produced and available locally. The production of serotonin requires a rate-limiting enzyme called tryptophan hydroxylase (TPH) that comes in two forms, TPH1 and TPH2. TPH1 produces serotonin in the periphery, while TPH2 controls serotonin production by serotonergic neurons in the brain. To determine which source of serotonin is most important for HSPC formation, Kwan et al. (2016) performed morpholino knockdowns of the TPH1 (tph1a and tph1b) and TPH2 (tph2) genes. All knockdowns
decreased blood cell production in the dorsal aorta. Surprisingly, knockdown of tph2, which is responsible for the production of serotonin in the brain, caused the most sustained reduction in HSPCs. Kwan et al. (2016) elucidated the pathway by which serotonin production in the brain influenced HSPC production in the dorsal aorta. Neurotransmission by serotonin is relayed to the periphery via two pathways, the sympathetic nervous system and the hypothalamic, pituitary, adrenal (interrenal) axis (HPA/I). The HPA/I axis is essentially a cascade of secreted hormones: serotonin binds to 5-hydroxytryptamine (5-HT) receptors on neurons in the hypothalamus and stimulates the release of corticotropin-releasing hormone; corticotropinreleasing hormone stimulates the pituitary to produce adrenocorticotropic hormone; adrenocorticotropic hormone causes the adrenal gland to produce glucocorticoids; and glucocorticoids bind and activate glucocorticoid receptors (Figure 1). Glucocorticoid receptors are widely expressed in the zebrafish embryo, including in hemogenic endothelium and HSPCs. Through a combination of morpholino knockdowns, genetic mutants, small-molecule agonists, and epistasis analyses, Kwan et al. (2016) demonstrate that each component of the HPA/I axis (TPH2, corticotropin-releasing hormone receptor, adenocorticotropic hormone, glucocorticoid receptor) is necessary to relay the serotonin signal from the brain to promote HSPC formation in the dorsal aorta. The HPA/I axis is normally activated in response to stress, including social/ behavioral stress and physiological stress. At the time HSPCs form in the aorta the embryo does not yet experience social or behavioral stress, but it does
Cell Stem Cell 19, September 1, 2016 ª 2016 Elsevier Inc. 279
Cell Stem Cell
Previews
perceive and respond to tion factor result in enduring developmental stress. Kwan epigenetic alterations in emet al. (2016) showed that bryonic HSPCs that persist developmental stress, specifin adult HSCs? Regardless ically hypoxia, could activate of the answers, the results the HPA/I axis in the zebrafish of Kwan et al. (2016) illustrate embryo through the activation again that pathways other of hypoxia inducible factor 1 a than the ones we normally (Hif1a) in the brain, which in associate with development turn induced tph2 transcripare important players in tion and serotonin producembryogenesis. Figure 1. Stress-Induced Promotion of HSPC Formation in the Dorsal Aorta through the HPA/I Axis tion. Although hypoxia was The image represents a zebrafish embryo with each step of the pathway and the only stress-inducing stimREFERENCES its anatomic location illustrated using the same colors. The location of HSPC ulus tested, it is conceivable production in the dorsal aorta (red) is surrounded by a rectangle. Adamo, L., Naveiras, O., Wenzel, that other common stresses P.L., McKinney-Freeman, S., Mack, that the embryo experiences P.J., Gracia-Sancho, J., Suchysuch as temperature, metabolic, or oxida- additionally regulate HSPCs in the bone Dicey, A., Yoshimoto, M., Lensch, M.W., Yoder, M.C., et al. (2009). Nature 459, 1131–1135. tive stress would also promote blood cell marrow through that mechanism. formation through the HPA/I axis. Good stress plays an essential role in Burns, C.E., Galloway, J.L., Smith, A.C., Keefe, Other examples of neuronal regulation physiology and evolution. The fight-or- M.D., Cashman, T.J., Paik, E.J., Mayhall, E.A., A.H., and Zon, L.I. (2009). Blood of hematopoiesis have been described. flight response is a reaction to acute, Amsterdam, 113, 5776–5782. For example the sympathetic nervous good stress that enables prey to escape system releases catecholamines in the a predator. Good stress enhances the Clements, W.K., and Traver, D. (2013). Nat. Rev. Immunol. 13, 336–348. vicinity of the dorsal aorta to promote immune and wound healing responses, HSPC formation in the embryo (Fitch which from a survival standpoint is Dhabhar, F.S. (2014). Immunol. Res. 58, 193–210. et al., 2012). In the adult, circadian important for the prey that did not Fitch, S.R., Kimber, G.M., Wilson, N.K., Parker, A., rhythms, which are relayed from the cen- escape the predator unscathed (Dhab- Mirshekar-Syahkal, B., Go¨ttgens, B., Medvinsky, tral pacemaker in the brain through the har, 2014). Although the benefit of A., Dzierzak, E., and Ottersbach, K. (2012). Cell sympathetic nervous system, regulate mounting a stress response in the adult Stem Cell 11, 554–566. the numbers of HSPCs that are mobilized is clear, is there is an evolutionary advan- Kwan, W., Cortes, M., Frost, I., Esain, V., Theointo the blood stream through the release tage to having blood formation in the dore, L.N., Liu, S.Y., Budrow, N., Goessling, W., and North, T.E. (2016). Cell Stem Cell 19, this issue, of noradrenalines in the bone marrow embryo enhanced by stress? Or, is the 370–382. (Me´ndez-Ferrer et al., 2008). However in HSPC response to developmental stress both of these cases neurons are thought merely an ancillary outcome of an essen- Me´ndez-Ferrer, S., Lucas, D., Battista, M., and Frenette, P.S. (2008). Nature 452, 442–447. to release a neurotransmitter directly into tial stress pathway in the adult that is the HSPC niche, whereas the HPA/I axis wired in the embryo? Another topic North, T.E., Goessling, W., Walkley, C.R., Lengerke, C., Kopani, K.R., Lord, A.M., Weber, relies on a neurotransmitter in the brain worth considering is that Kwan et al. G.J., Bowman, T.V., Jang, I.H., Grosser, T., et al. that activates a relay of hormones deliv- (2016) reported the effect of the HPA/I (2007). Nature 447, 1007–1011. ered through the circulation to the site of axis on the expansion of embryonic North, T.E., Goessling, W., Peeters, M., Li, P., Ceol, HSPC formation. Interestingly, circadian HSPCs. However, the HPA/I path- C., Lord, A.M., Weber, G.J., Harris, J., Cutting, rhythms also activate glucocorticoid pro- way ends with the activation of a C.C., Huang, P., et al. (2009). Cell 137, 736–748. duction through the HPA/I axis, raising transcription factor, the glucocorticoid Tober, J., Maijenburg, M.W., and Speck, N.A. the possibility that circadian rhythms receptor. Does activation of a transcrip- (2016). Curr. Top. Dev. Biol. 118, 113–162.
280 Cell Stem Cell 19, September 1, 2016
Previews Stress Can Be a Good Thing for Blood Formation Nancy A. Speck1,* 1Abramson Family Cancer Research Institute, Department of Cell and Developmental Biology, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.stem.2016.08.011
Like politics, most developmental signals are local. However, in this issue of Cell Stem Cell, Kwan et al. (2016) and colleagues describe how a stress-induced signal that originates in the zebrafish brain promotes the formation of blood at a distant site, the dorsal aorta. Multiple signaling pathways are required to produce blood cells in the embryo, including the Notch, Wnt, Hedgehog, bone morphogenic protein (BMP), and fibroblast growth factor pathways (Clements and Traver, 2013). These signals are generally delivered locally, for example on the plasma membrane of adjacent cells (Notch), or are secreted and diffuse over modest distances (Wnt, BMP, and Hedgehog). However, some signals travel long distances through the circulation to regulate blood cell formation. In this issue of Cell Stem Cell, Kwan et al., (2016) report that a pathway activated by stress in the brain promotes hematopoietic stem and progenitor cell (HSPC) formation at a distance in the dorsal aorta of zebrafish embryos. An important site of blood formation in the embryo, particularly for the development of hematopoietic stem cells, is the dorsal aorta, which contains a transient population of blood-producing endothelial cells called hemogenic endothelium (Tober et al., 2016). At approximately embryonic days 10.5–11.5 in the mouse, embryonic days 27–40 in the human, and 30–54 hr post-fertilization in zebrafish embryos, hemogenic endothelial cells undergo an endothelial to hematopoietic transition (EHT), similar to the more well-known epithelial to mesenchymal transition (EMT), and become HSPCs. The HSPCs then enter the circulation and colonize the fetal liver, and later the bone marrow, in mouse and human embryos. The transcription factor Runx1 is expressed in the hemogenic endothelium and is required for the EHT (Tober et al., 2016). By monitoring the expression of Runx1, and also that of the transcription factor Myb, which is expressed shortly after Runx1 in HSPCs, various groups have identified small molecules, genes,
or physical processes that enhance or inhibit HSPC formation (Adamo et al., 2009; Burns et al., 2009; North et al., 2007, 2009). The zebrafish embryo is particularly well suited for these types of analyses for multiple reasons, one of which is that signals that normally originate from a distant site in the embryo can be identified. A previous chemical genetic screen of small molecules using zebrafish embryos identified neuroregulators that could increase Runx1 and Myb expression and HSPC formation in the dorsal aorta (North et al., 2007). In this issue, Kwan et al. (2016) determine the mechanism by which one of these regulators, serotonin, enhances HSPC formation. Serotonin is a monoamine derived from tryptophan. The vast majority of serotonin in the zebrafish embryo is produced in the periphery (skin, gut, and pineal gland), where it regulates many physiological functions including gut motility, cardiac function, and platelet aggregation. Serotonin is also produced in the brain, where it functions as a neurotransmitter that regulates mood, appetite, sleep, and stress. Intuitively, one would expect that peripheral serotonin would be the most important regulator of HSPC formation in the dorsal aorta since it is produced and available locally. The production of serotonin requires a rate-limiting enzyme called tryptophan hydroxylase (TPH) that comes in two forms, TPH1 and TPH2. TPH1 produces serotonin in the periphery, while TPH2 controls serotonin production by serotonergic neurons in the brain. To determine which source of serotonin is most important for HSPC formation, Kwan et al. (2016) performed morpholino knockdowns of the TPH1 (tph1a and tph1b) and TPH2 (tph2) genes. All knockdowns
decreased blood cell production in the dorsal aorta. Surprisingly, knockdown of tph2, which is responsible for the production of serotonin in the brain, caused the most sustained reduction in HSPCs. Kwan et al. (2016) elucidated the pathway by which serotonin production in the brain influenced HSPC production in the dorsal aorta. Neurotransmission by serotonin is relayed to the periphery via two pathways, the sympathetic nervous system and the hypothalamic, pituitary, adrenal (interrenal) axis (HPA/I). The HPA/I axis is essentially a cascade of secreted hormones: serotonin binds to 5-hydroxytryptamine (5-HT) receptors on neurons in the hypothalamus and stimulates the release of corticotropin-releasing hormone; corticotropinreleasing hormone stimulates the pituitary to produce adrenocorticotropic hormone; adrenocorticotropic hormone causes the adrenal gland to produce glucocorticoids; and glucocorticoids bind and activate glucocorticoid receptors (Figure 1). Glucocorticoid receptors are widely expressed in the zebrafish embryo, including in hemogenic endothelium and HSPCs. Through a combination of morpholino knockdowns, genetic mutants, small-molecule agonists, and epistasis analyses, Kwan et al. (2016) demonstrate that each component of the HPA/I axis (TPH2, corticotropin-releasing hormone receptor, adenocorticotropic hormone, glucocorticoid receptor) is necessary to relay the serotonin signal from the brain to promote HSPC formation in the dorsal aorta. The HPA/I axis is normally activated in response to stress, including social/ behavioral stress and physiological stress. At the time HSPCs form in the aorta the embryo does not yet experience social or behavioral stress, but it does
Cell Stem Cell 19, September 1, 2016 ª 2016 Elsevier Inc. 279
Cell Stem Cell
Previews
perceive and respond to tion factor result in enduring developmental stress. Kwan epigenetic alterations in emet al. (2016) showed that bryonic HSPCs that persist developmental stress, specifin adult HSCs? Regardless ically hypoxia, could activate of the answers, the results the HPA/I axis in the zebrafish of Kwan et al. (2016) illustrate embryo through the activation again that pathways other of hypoxia inducible factor 1 a than the ones we normally (Hif1a) in the brain, which in associate with development turn induced tph2 transcripare important players in tion and serotonin producembryogenesis. Figure 1. Stress-Induced Promotion of HSPC Formation in the Dorsal Aorta through the HPA/I Axis tion. Although hypoxia was The image represents a zebrafish embryo with each step of the pathway and the only stress-inducing stimREFERENCES its anatomic location illustrated using the same colors. The location of HSPC ulus tested, it is conceivable production in the dorsal aorta (red) is surrounded by a rectangle. Adamo, L., Naveiras, O., Wenzel, that other common stresses P.L., McKinney-Freeman, S., Mack, that the embryo experiences P.J., Gracia-Sancho, J., Suchysuch as temperature, metabolic, or oxida- additionally regulate HSPCs in the bone Dicey, A., Yoshimoto, M., Lensch, M.W., Yoder, M.C., et al. (2009). Nature 459, 1131–1135. tive stress would also promote blood cell marrow through that mechanism. formation through the HPA/I axis. Good stress plays an essential role in Burns, C.E., Galloway, J.L., Smith, A.C., Keefe, Other examples of neuronal regulation physiology and evolution. The fight-or- M.D., Cashman, T.J., Paik, E.J., Mayhall, E.A., A.H., and Zon, L.I. (2009). Blood of hematopoiesis have been described. flight response is a reaction to acute, Amsterdam, 113, 5776–5782. For example the sympathetic nervous good stress that enables prey to escape system releases catecholamines in the a predator. Good stress enhances the Clements, W.K., and Traver, D. (2013). Nat. Rev. Immunol. 13, 336–348. vicinity of the dorsal aorta to promote immune and wound healing responses, HSPC formation in the embryo (Fitch which from a survival standpoint is Dhabhar, F.S. (2014). Immunol. Res. 58, 193–210. et al., 2012). In the adult, circadian important for the prey that did not Fitch, S.R., Kimber, G.M., Wilson, N.K., Parker, A., rhythms, which are relayed from the cen- escape the predator unscathed (Dhab- Mirshekar-Syahkal, B., Go¨ttgens, B., Medvinsky, tral pacemaker in the brain through the har, 2014). Although the benefit of A., Dzierzak, E., and Ottersbach, K. (2012). Cell sympathetic nervous system, regulate mounting a stress response in the adult Stem Cell 11, 554–566. the numbers of HSPCs that are mobilized is clear, is there is an evolutionary advan- Kwan, W., Cortes, M., Frost, I., Esain, V., Theointo the blood stream through the release tage to having blood formation in the dore, L.N., Liu, S.Y., Budrow, N., Goessling, W., and North, T.E. (2016). Cell Stem Cell 19, this issue, of noradrenalines in the bone marrow embryo enhanced by stress? Or, is the 370–382. (Me´ndez-Ferrer et al., 2008). However in HSPC response to developmental stress both of these cases neurons are thought merely an ancillary outcome of an essen- Me´ndez-Ferrer, S., Lucas, D., Battista, M., and Frenette, P.S. (2008). Nature 452, 442–447. to release a neurotransmitter directly into tial stress pathway in the adult that is the HSPC niche, whereas the HPA/I axis wired in the embryo? Another topic North, T.E., Goessling, W., Walkley, C.R., Lengerke, C., Kopani, K.R., Lord, A.M., Weber, relies on a neurotransmitter in the brain worth considering is that Kwan et al. G.J., Bowman, T.V., Jang, I.H., Grosser, T., et al. that activates a relay of hormones deliv- (2016) reported the effect of the HPA/I (2007). Nature 447, 1007–1011. ered through the circulation to the site of axis on the expansion of embryonic North, T.E., Goessling, W., Peeters, M., Li, P., Ceol, HSPC formation. Interestingly, circadian HSPCs. However, the HPA/I path- C., Lord, A.M., Weber, G.J., Harris, J., Cutting, rhythms also activate glucocorticoid pro- way ends with the activation of a C.C., Huang, P., et al. (2009). Cell 137, 736–748. duction through the HPA/I axis, raising transcription factor, the glucocorticoid Tober, J., Maijenburg, M.W., and Speck, N.A. the possibility that circadian rhythms receptor. Does activation of a transcrip- (2016). Curr. Top. Dev. Biol. 118, 113–162.
280 Cell Stem Cell 19, September 1, 2016