- Email: [email protected]
Mutualism in the Marrow
Cell Stem Cell
Previews brain parenchyma must be finely tuned and alterations of this homeostasis can have long-ranging effects. The importance of such a lactate homeostasis is also evident when looking at the effects of lactate accumulation on general hippocampal cognition described in this study. While mature neurons utilize lactate as an energy substrate, too much lactate seems to impair their function. Interestingly, aging brains have higher brain lactate levels and several neurodegenerative diseases are accompanied by metabolic alterations (Camandola and Mattson, 2017), which might contribute to cognitive impairments. Taken together, these studies suggest that the metabolic microenvironment may be a critical regulator and target for ameliorated cognitive performance and neurogenesis.
L-Lactate Promotes Adult Hippocampal Neurogenesis. Front. Neurosci. 13, 403.
REFERENCES Camandola, S., and Mattson, M.P. (2017). Brain metabolism in health, aging, and neurodegeneration. EMBO J. 36, 1474–1492. Chandel, N.S., Jasper, H., Ho, T.T., and Passegue´, E. (2016). Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat. Cell Biol. 18, 823–832. Cooper, C., Moon, H.Y., and van Praag, H. (2018). On the Run for Hippocampal Plasticity. Cold Spring Harb. Perspect. Med. 8, a029736. Ito, K., and Suda, T. (2014). Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243–256. Knobloch, M., and Jessberger, S. (2017). Metabolism and neurogenesis. Curr. Opin. Neurobiol. 42, 45–52. Lev-Vachnish, Y., Cadury, S., Rotter-Maskowitz, A., Feldman, N., Roichman, A., Illouz, T., Varvak, A., Nicola, R., Madar, R., and Okun, E. (2019).
Magistretti, P.J., and Allaman, I. (2018). Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249. Morland, C., Andersson, K.A., Haugen, Ø.P., Hadzic, A., Kleppa, L., Gille, A., Rinholm, J.E., Palibrk, V., Diget, E.H., Kennedy, L.H., et al. (2017). Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat. Commun. 8, 15557. Pe´rez-Escuredo, J., Van He´e, V.F., Sboarina, M., Falces, J., Payen, V.L., Pellerin, L., and Sonveaux, P. (2016). Monocarboxylate transporters in the brain and in cancer. Biochim. Biophys. Acta 1863, 2481–2497. Wang, J., Cui, Y., Yu, Z., Wang, W., Cheng, X., Ji, W., Guo, S., Zhou, Q., Wu, N., Chen, Y., et al. (2019). Brain endothelial cells maintain lactate homeostasis and control adult hippocampal neurogenesis. Cell Stem Cell 25, this issue, 754–767.
Mutualism in the Marrow John P. Chute1,2,3,* and Christina M. Termini1 1Division
of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA, USA and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA 3Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA *Correspondence: [email protected] https://doi.org/10.1016/j.stem.2019.11.007 2Eli
Cross-talk between hematopoietic stem cells (HSCs) and the HSC niche is likely important in hematopoiesis but not well demonstrated. Now in Cell Stem Cell, Chen et al. (2019) describe how specialized endothelial cells regulate hematopoietic stem cell maintenance and how hematopoietic stem/progenitor cells facilitate vascular regeneration in return. Bone marrow endothelial cells (BM ECs) are essential for hematopoietic regeneration to occur following myelosuppressive insults such as chemotherapy and total body irradiation (TBI) (Hooper et al., 2009). EC-derived paracrine factors, including Jagged-1, pleiotrophin, and epidermal growth factor, have important functions in promoting hematopoietic regeneration in vivo (Doan et al., 2013; Himburg et al., 2018; Poulos et al., 2013). While important research has focused on the discovery of proteins produced by ECs and other BM niche cells that regulate hematopoietic regeneration following myelosuppression (Zhou et al., 2017; Goncalves et al., 2016), less is known about the pre-
cise subpopulations of BM ECs that contribute to vascular and hematopoietic regeneration following myelosuppressive injury. In this issue of Cell Stem Cell, Chen et al. (2019) demonstrate that TBI or 5-fluorouracil (5-FU) chemotherapy disrupts and dilates BM capillaries, expands BM vascular area, and causes an increase in BM EC density and vascular permeability within 7 days. Interestingly, BM EC apoptosis was not increased at 24 h after TBI, suggesting that gross degradation of the BM vasculature occurs in the absence of EC programmed cell death. RNA sequence analysis of BM ECs revealed that the EC transcriptome in irradi-
ated mice was markedly different than that of BM ECs from non-irradiated mice, with particular loss of several molecular signals important in EC-mediated maintenance of HSCs, such as stem cell factor, CXCL12, Angiopoietin 1, and pleiotrophin. Notably, the expression of genes involved in DNA damage and senescence was not significantly altered in BM ECs in irradiated mice as compared with non-irradiated animals. Since radiation and chemotherapy deplete hematopoietic cells in the BM, the authors hypothesized that the loss of hematopoietic cells might contribute critically to the vascular defects observed in myelosuppressed mice. Using a
Cell Stem Cell 25, December 5, 2019 ª 2019 Elsevier Inc. 731
Cell Stem Cell
Previews
Figure 1. Cross-Talk between Apelin+ ECs and Hematopoietic Stem/Progenitor Cells in Homeostasis and Regeneration The triangle shows distinct phases of interaction between HSPCs and the BM vasculature during homeostasis, hematopoietic cell depletion, vascular regeneration, and HSC transplantation. HSC, hematopoietic stem cell; EC, endothelial cell; VEGF A, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor 2; TBI, total body irradiation.
diphtheria-toxin-mediated approach, the authors showed that depletion of Vav1expressing hematopoietic cells caused the expansion of the BM vascular area, dilated sinusoidal vessels, increased BM EC density, and increased BM vascular permeability, essentially phenocopying the effects of TBI or chemotherapy administration. Moreover, depletion of BM hematopoietic cells caused the downregulation of expression of several EC nicherelated genes. These results suggest that hematopoietic cells have an essential role in maintaining the structural and functional integrity of the BM vasculature. In keeping with these findings, transplantation of BM lin-sca-1+ckit+ (LSK) hematopoietic stem/ progenitor cells (HSPCs) promoted the reestablishment of normal BM vascular organization in irradiated mice, whereas transplantation of BM lin cells or lin+ cells was less effective. A prior study by Zhou et al. demonstrated that deletion of Angiopoietin 1 from BM hematopoietic cells promoted vascular and hematopoietic recovery in mice after irradiation (Zhou et al., 2015). 732 Cell Stem Cell 25, December 5, 2019
Here, the data suggest that HSPCs promote BM vascular recovery following irradiation via yet to be determined mechanisms. Utilizing genetic labeling techniques, the authors explored which populations of BM ECs contribute to BM vascular regeneration following TBI. The morphology of BM arteries was not significantly altered by TBI or chemotherapy and arterial ECs did not contribute to regenerating BM sinusoidal vessels after irradiation and BM transplantation. However, genetic labeling of BM ECs expressing Apelin, a peptide secreted by a subset of angiogenic ECs (Tian et al., 2013), identified a unique EC population in the BM that co-localized with HSCs and strongly expressed HSC growth factors. Diphtheria-toxin-mediated ablation of Apelin+ BM ECs disrupted and dilated BM sinusoidal vessels, increased vascular permeability, and substantially reduced numbers of BM hematopoietic progenitor cells and HSCs capable of competitive repopulation in mice. Therefore, Apelin+ ECs are required for mainte-
nance of HSCs and hematopoietic progenitor cells in the BM. Deletion of stem cell factor and VEGF receptor 2 in Apelin+ ECs also caused reductions in HSC numbers, confirming that Apelin+ ECs provide essential signaling that promotes HSC maintenance in vivo. Importantly, the authors also characterized the function of Apelin+ BM ECs in regulating BM transplantation and vascular regeneration following TBI. Recipient mice lacking Apelin+ ECs displayed substantially decreased engraftment of donor BM hematopoietic cells following TBI compared to recipient mice with Apelin-expressing ECs. In complementary studies, the authors found that Apelin+ ECs increased substantially following TBI and contributed to the majority of regenerated vessels in the BM. In order to confirm that the contributions of Apelin+ ECs were unique, the authors ablated a different BM EC population, endothelial-cell-specific molecule 1 (Esm1)-expressing ECs, which label a percentage of BM ECs that is similar to that of Apelin+ BM ECs. Ablation of Esm1+ ECs had no effect on steady-state hematopoiesis and Esm1+ ECs did not expand significantly after TBI to contribute to BM vascular regeneration. These results suggest that Apelin+ BM ECs represent a distinct BM EC subpopulation that regulates hematopoiesis and vascular regeneration following myelotoxicity. Finally, the authors evaluated whether cross-talk between BM HSPCs and Apelin+ BM ECs contributes to vascular or hematopoietic regeneration following TBI. For this question, the authors focused on VEGF-VEGFR2 signaling, since HSPCs produce VEGF-A and VEGFR2 is expressed by both hematopoietic cells and BM ECs. Deletion of VEGFR2 in donor hematopoietic cells had no effect on engraftment following BM transplantation, but deletion of VEGFR2 in Apelin+ ECs caused delayed BM vascular recovery and decreased BM HSPCs, myeloid cells, and B cells following BM transplantation. Conversely, systemic administration of VEGF-A increased the percentages of Apelin+ ECs in the BM, promoted the normalization of the BM vasculature, and increased HSC frequency and donor hematopoietic cell engraftment in irradiated, transplanted mice. This study provides fascinating insights into the function of Apelin+ BM ECs in contributing to BM vascular regeneration
Cell Stem Cell
Previews and regulating both steady-state hematopoiesis and hematopoietic reconstitution following transplantation. This work also reveals a mutual and instructive role for HSPCs in maintaining the integrity of the BM vasculature, mediated at least in part via hematopoietic-cell-derived VEGF-A action on Apelin+ BM ECs (Figure 1). Important questions are raised by these findings: do Apelin+ BM ECs control endogenous hematopoietic regeneration following chemotherapy or radiation injury? What are the molecular mechanisms through which Apelin+ BM ECs regulate hematopoiesis and does cross-talk occur between HSC-supportive BM stromal cells and Apelin+ BM ECs? One hundred and fifty years ago, Pierre Joseph van Beneden introduced the concept of biological mutualism, in which two organisms provide and receive benefits from each other (van Beneden, 1876). We now know that cellular mutualism exists in the bone marrow via the relation-
REFERENCES
Hooper, A.T., Butler, J.M., Nolan, D.J., Kranz, A., Iida, K., Kobayashi, M., Kopp, H.G., Shido, K., Petit, I., Yanger, K., et al. (2009). Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4, 263–274.
Chen, Q., Liu, Y., Jeong, H., Stehling, M., Dinh, V., Zhou, B., and Adams, R.H. (2019). Apelin+ endothelial cells control hematopoiesis and mediate vascular regeneration after myeloablative injury. Cell Stem Cell 25, this issue, 768–783.
Poulos, M.G., Guo, P., Kofler, N.M., Pinho, S., Gutkin, M.C., Tikhonova, A., Aifantis, I., Frenette, P.S., Kitajewski, J., Rafii, S., and Butler, J.M. (2013). Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep. 4, 1022–1034.
Doan, P.L., Himburg, H.A., Helms, K., Russell, J.L., Fixsen, E., Quarmyne, M., Harris, J.R., Deoliviera, D., Sullivan, J.M., Chao, N.J., et al. (2013). Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat. Med. 19, 295–304.
Tian, X., Hu, T., Zhang, H., He, L., Huang, X., Liu, Q., Yu, W., He, L., Yang, Z., Zhang, Z., et al. (2013). Subepicardial endothelial cells invade the embryonic ventricle wall to form coronary arteries. Cell Res. 23, 1075–1090.
ship of hematopoietic cells with their EC neighbors.
Goncalves, K.A., Silberstein, L., Li, S., Severe, N., Hu, M.G., Yang, H., Scadden, D.T., and Hu, G.F. (2016). Angiogenin promotes hematopoietic regeneration by dichotomously regulating quiescence of stem and progenitor cells. Cell 166, 894–906. Himburg, H.A., Termini, C.M., Schlussel, L., Kan, J., Li, M., Zhao, L., Fang, T., Sasine, J.P., Chang, V.Y., and Chute, J.P. (2018). Distinct bone marrow sources of pleiotrophin control hematopoietic stem cell maintenance and regeneration. Cell Stem Cell 23, 370–381.e5.
van Beneden, P.J. (1876). Animal Parasites and Messmates, Third Edition (London: Henry S. King). Zhou, B.O., Ding, L., and Morrison, S.J. (2015). Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1. eLife 4, e05521. Zhou, B.O., Yue, R., Rios, J.J., Naveiras, O., and Morrison, S.J. (2017). Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat. Cell. Biol. 19, 891–903.
The Seed Tends to the Soil: Hair Follicle Stem Cells Remodel Their Lymphatic Niche Denise Gay1,2,* and Mayumi Ito1,2,* 1The
Ronald O. Perelman Department of Dermatology, New York University, School of Medicine, New York, NY 10016, USA of Cell Biology, New York University, School of Medicine, New York, NY 10016, USA *Correspondence: [email protected] (D.G.), [email protected] (M.I.) https://doi.org/10.1016/j.stem.2019.11.009 2Department
Hair follicle stem cells may themselves regulate the niche environment for hair follicle regrowth. A recent Science paper from Elaine Fuchs and colleagues (Gur-Cohen et al., 2019) suggests that this involves regulation of the lymphatic system and may have implications in understanding tissue regeneration. Hair follicles (HFs) undergo rounds of regeneration throughout the life of the individual. Each regenerative cycle includes distinct phases, namely, degeneration of the lower follicle (catagen), followed by a quiescent period (telogen), and then regrowth (anagen) to yield a new lower follicle replete with new hair shaft. Stem cells (SCs) located within a specialized region in the upper follicle, the bulge, fuel this regenerative process. It is believed that the environment around these cells, termed the niche, supports
their maintenance, i.e., their dual capacity for self-renewal and differentiation (Myung and Ito, 2012). Gur-Cohen et al. (2019) report the important finding that not only does lymphatic vasculature adjacent to the telogen bulge provide essential support for HFSC quiescence, but also that activated HFSCs cyclically remodel the lymphatics to promote anagen onset leading to hair regeneration (Figure 1). That SCs may contribute to the establishment of their vascular niche has previ-
ously been explored in hematopoietic stem cell (HSC) development and maintenance within the bone marrow (Morrison and Scadden, 2014; Boulais and Frenette, 2015). It is known that vasculature, including perivascular and endothelial cells, contributes to HSC self-renewal for homeostatic and regenerative hematopoiesis. Intriguingly, HSCs may play a role in shaping this vascular niche during development. Takakura et al. (2000) found that AML1-deficient embryos that completely lack HSCs also exhibit defective
Cell Stem Cell 25, December 5, 2019 ª 2019 Elsevier Inc. 733
Previews brain parenchyma must be finely tuned and alterations of this homeostasis can have long-ranging effects. The importance of such a lactate homeostasis is also evident when looking at the effects of lactate accumulation on general hippocampal cognition described in this study. While mature neurons utilize lactate as an energy substrate, too much lactate seems to impair their function. Interestingly, aging brains have higher brain lactate levels and several neurodegenerative diseases are accompanied by metabolic alterations (Camandola and Mattson, 2017), which might contribute to cognitive impairments. Taken together, these studies suggest that the metabolic microenvironment may be a critical regulator and target for ameliorated cognitive performance and neurogenesis.
L-Lactate Promotes Adult Hippocampal Neurogenesis. Front. Neurosci. 13, 403.
REFERENCES Camandola, S., and Mattson, M.P. (2017). Brain metabolism in health, aging, and neurodegeneration. EMBO J. 36, 1474–1492. Chandel, N.S., Jasper, H., Ho, T.T., and Passegue´, E. (2016). Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat. Cell Biol. 18, 823–832. Cooper, C., Moon, H.Y., and van Praag, H. (2018). On the Run for Hippocampal Plasticity. Cold Spring Harb. Perspect. Med. 8, a029736. Ito, K., and Suda, T. (2014). Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243–256. Knobloch, M., and Jessberger, S. (2017). Metabolism and neurogenesis. Curr. Opin. Neurobiol. 42, 45–52. Lev-Vachnish, Y., Cadury, S., Rotter-Maskowitz, A., Feldman, N., Roichman, A., Illouz, T., Varvak, A., Nicola, R., Madar, R., and Okun, E. (2019).
Magistretti, P.J., and Allaman, I. (2018). Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci. 19, 235–249. Morland, C., Andersson, K.A., Haugen, Ø.P., Hadzic, A., Kleppa, L., Gille, A., Rinholm, J.E., Palibrk, V., Diget, E.H., Kennedy, L.H., et al. (2017). Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat. Commun. 8, 15557. Pe´rez-Escuredo, J., Van He´e, V.F., Sboarina, M., Falces, J., Payen, V.L., Pellerin, L., and Sonveaux, P. (2016). Monocarboxylate transporters in the brain and in cancer. Biochim. Biophys. Acta 1863, 2481–2497. Wang, J., Cui, Y., Yu, Z., Wang, W., Cheng, X., Ji, W., Guo, S., Zhou, Q., Wu, N., Chen, Y., et al. (2019). Brain endothelial cells maintain lactate homeostasis and control adult hippocampal neurogenesis. Cell Stem Cell 25, this issue, 754–767.
Mutualism in the Marrow John P. Chute1,2,3,* and Christina M. Termini1 1Division
of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA, USA and Edythe Broad Stem Cell Research Center, UCLA, Los Angeles, CA, USA 3Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, USA *Correspondence: [email protected] https://doi.org/10.1016/j.stem.2019.11.007 2Eli
Cross-talk between hematopoietic stem cells (HSCs) and the HSC niche is likely important in hematopoiesis but not well demonstrated. Now in Cell Stem Cell, Chen et al. (2019) describe how specialized endothelial cells regulate hematopoietic stem cell maintenance and how hematopoietic stem/progenitor cells facilitate vascular regeneration in return. Bone marrow endothelial cells (BM ECs) are essential for hematopoietic regeneration to occur following myelosuppressive insults such as chemotherapy and total body irradiation (TBI) (Hooper et al., 2009). EC-derived paracrine factors, including Jagged-1, pleiotrophin, and epidermal growth factor, have important functions in promoting hematopoietic regeneration in vivo (Doan et al., 2013; Himburg et al., 2018; Poulos et al., 2013). While important research has focused on the discovery of proteins produced by ECs and other BM niche cells that regulate hematopoietic regeneration following myelosuppression (Zhou et al., 2017; Goncalves et al., 2016), less is known about the pre-
cise subpopulations of BM ECs that contribute to vascular and hematopoietic regeneration following myelosuppressive injury. In this issue of Cell Stem Cell, Chen et al. (2019) demonstrate that TBI or 5-fluorouracil (5-FU) chemotherapy disrupts and dilates BM capillaries, expands BM vascular area, and causes an increase in BM EC density and vascular permeability within 7 days. Interestingly, BM EC apoptosis was not increased at 24 h after TBI, suggesting that gross degradation of the BM vasculature occurs in the absence of EC programmed cell death. RNA sequence analysis of BM ECs revealed that the EC transcriptome in irradi-
ated mice was markedly different than that of BM ECs from non-irradiated mice, with particular loss of several molecular signals important in EC-mediated maintenance of HSCs, such as stem cell factor, CXCL12, Angiopoietin 1, and pleiotrophin. Notably, the expression of genes involved in DNA damage and senescence was not significantly altered in BM ECs in irradiated mice as compared with non-irradiated animals. Since radiation and chemotherapy deplete hematopoietic cells in the BM, the authors hypothesized that the loss of hematopoietic cells might contribute critically to the vascular defects observed in myelosuppressed mice. Using a
Cell Stem Cell 25, December 5, 2019 ª 2019 Elsevier Inc. 731
Cell Stem Cell
Previews
Figure 1. Cross-Talk between Apelin+ ECs and Hematopoietic Stem/Progenitor Cells in Homeostasis and Regeneration The triangle shows distinct phases of interaction between HSPCs and the BM vasculature during homeostasis, hematopoietic cell depletion, vascular regeneration, and HSC transplantation. HSC, hematopoietic stem cell; EC, endothelial cell; VEGF A, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor 2; TBI, total body irradiation.
diphtheria-toxin-mediated approach, the authors showed that depletion of Vav1expressing hematopoietic cells caused the expansion of the BM vascular area, dilated sinusoidal vessels, increased BM EC density, and increased BM vascular permeability, essentially phenocopying the effects of TBI or chemotherapy administration. Moreover, depletion of BM hematopoietic cells caused the downregulation of expression of several EC nicherelated genes. These results suggest that hematopoietic cells have an essential role in maintaining the structural and functional integrity of the BM vasculature. In keeping with these findings, transplantation of BM lin-sca-1+ckit+ (LSK) hematopoietic stem/ progenitor cells (HSPCs) promoted the reestablishment of normal BM vascular organization in irradiated mice, whereas transplantation of BM lin cells or lin+ cells was less effective. A prior study by Zhou et al. demonstrated that deletion of Angiopoietin 1 from BM hematopoietic cells promoted vascular and hematopoietic recovery in mice after irradiation (Zhou et al., 2015). 732 Cell Stem Cell 25, December 5, 2019
Here, the data suggest that HSPCs promote BM vascular recovery following irradiation via yet to be determined mechanisms. Utilizing genetic labeling techniques, the authors explored which populations of BM ECs contribute to BM vascular regeneration following TBI. The morphology of BM arteries was not significantly altered by TBI or chemotherapy and arterial ECs did not contribute to regenerating BM sinusoidal vessels after irradiation and BM transplantation. However, genetic labeling of BM ECs expressing Apelin, a peptide secreted by a subset of angiogenic ECs (Tian et al., 2013), identified a unique EC population in the BM that co-localized with HSCs and strongly expressed HSC growth factors. Diphtheria-toxin-mediated ablation of Apelin+ BM ECs disrupted and dilated BM sinusoidal vessels, increased vascular permeability, and substantially reduced numbers of BM hematopoietic progenitor cells and HSCs capable of competitive repopulation in mice. Therefore, Apelin+ ECs are required for mainte-
nance of HSCs and hematopoietic progenitor cells in the BM. Deletion of stem cell factor and VEGF receptor 2 in Apelin+ ECs also caused reductions in HSC numbers, confirming that Apelin+ ECs provide essential signaling that promotes HSC maintenance in vivo. Importantly, the authors also characterized the function of Apelin+ BM ECs in regulating BM transplantation and vascular regeneration following TBI. Recipient mice lacking Apelin+ ECs displayed substantially decreased engraftment of donor BM hematopoietic cells following TBI compared to recipient mice with Apelin-expressing ECs. In complementary studies, the authors found that Apelin+ ECs increased substantially following TBI and contributed to the majority of regenerated vessels in the BM. In order to confirm that the contributions of Apelin+ ECs were unique, the authors ablated a different BM EC population, endothelial-cell-specific molecule 1 (Esm1)-expressing ECs, which label a percentage of BM ECs that is similar to that of Apelin+ BM ECs. Ablation of Esm1+ ECs had no effect on steady-state hematopoiesis and Esm1+ ECs did not expand significantly after TBI to contribute to BM vascular regeneration. These results suggest that Apelin+ BM ECs represent a distinct BM EC subpopulation that regulates hematopoiesis and vascular regeneration following myelotoxicity. Finally, the authors evaluated whether cross-talk between BM HSPCs and Apelin+ BM ECs contributes to vascular or hematopoietic regeneration following TBI. For this question, the authors focused on VEGF-VEGFR2 signaling, since HSPCs produce VEGF-A and VEGFR2 is expressed by both hematopoietic cells and BM ECs. Deletion of VEGFR2 in donor hematopoietic cells had no effect on engraftment following BM transplantation, but deletion of VEGFR2 in Apelin+ ECs caused delayed BM vascular recovery and decreased BM HSPCs, myeloid cells, and B cells following BM transplantation. Conversely, systemic administration of VEGF-A increased the percentages of Apelin+ ECs in the BM, promoted the normalization of the BM vasculature, and increased HSC frequency and donor hematopoietic cell engraftment in irradiated, transplanted mice. This study provides fascinating insights into the function of Apelin+ BM ECs in contributing to BM vascular regeneration
Cell Stem Cell
Previews and regulating both steady-state hematopoiesis and hematopoietic reconstitution following transplantation. This work also reveals a mutual and instructive role for HSPCs in maintaining the integrity of the BM vasculature, mediated at least in part via hematopoietic-cell-derived VEGF-A action on Apelin+ BM ECs (Figure 1). Important questions are raised by these findings: do Apelin+ BM ECs control endogenous hematopoietic regeneration following chemotherapy or radiation injury? What are the molecular mechanisms through which Apelin+ BM ECs regulate hematopoiesis and does cross-talk occur between HSC-supportive BM stromal cells and Apelin+ BM ECs? One hundred and fifty years ago, Pierre Joseph van Beneden introduced the concept of biological mutualism, in which two organisms provide and receive benefits from each other (van Beneden, 1876). We now know that cellular mutualism exists in the bone marrow via the relation-
REFERENCES
Hooper, A.T., Butler, J.M., Nolan, D.J., Kranz, A., Iida, K., Kobayashi, M., Kopp, H.G., Shido, K., Petit, I., Yanger, K., et al. (2009). Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4, 263–274.
Chen, Q., Liu, Y., Jeong, H., Stehling, M., Dinh, V., Zhou, B., and Adams, R.H. (2019). Apelin+ endothelial cells control hematopoiesis and mediate vascular regeneration after myeloablative injury. Cell Stem Cell 25, this issue, 768–783.
Poulos, M.G., Guo, P., Kofler, N.M., Pinho, S., Gutkin, M.C., Tikhonova, A., Aifantis, I., Frenette, P.S., Kitajewski, J., Rafii, S., and Butler, J.M. (2013). Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep. 4, 1022–1034.
Doan, P.L., Himburg, H.A., Helms, K., Russell, J.L., Fixsen, E., Quarmyne, M., Harris, J.R., Deoliviera, D., Sullivan, J.M., Chao, N.J., et al. (2013). Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat. Med. 19, 295–304.
Tian, X., Hu, T., Zhang, H., He, L., Huang, X., Liu, Q., Yu, W., He, L., Yang, Z., Zhang, Z., et al. (2013). Subepicardial endothelial cells invade the embryonic ventricle wall to form coronary arteries. Cell Res. 23, 1075–1090.
ship of hematopoietic cells with their EC neighbors.
Goncalves, K.A., Silberstein, L., Li, S., Severe, N., Hu, M.G., Yang, H., Scadden, D.T., and Hu, G.F. (2016). Angiogenin promotes hematopoietic regeneration by dichotomously regulating quiescence of stem and progenitor cells. Cell 166, 894–906. Himburg, H.A., Termini, C.M., Schlussel, L., Kan, J., Li, M., Zhao, L., Fang, T., Sasine, J.P., Chang, V.Y., and Chute, J.P. (2018). Distinct bone marrow sources of pleiotrophin control hematopoietic stem cell maintenance and regeneration. Cell Stem Cell 23, 370–381.e5.
van Beneden, P.J. (1876). Animal Parasites and Messmates, Third Edition (London: Henry S. King). Zhou, B.O., Ding, L., and Morrison, S.J. (2015). Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1. eLife 4, e05521. Zhou, B.O., Yue, R., Rios, J.J., Naveiras, O., and Morrison, S.J. (2017). Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat. Cell. Biol. 19, 891–903.
The Seed Tends to the Soil: Hair Follicle Stem Cells Remodel Their Lymphatic Niche Denise Gay1,2,* and Mayumi Ito1,2,* 1The
Ronald O. Perelman Department of Dermatology, New York University, School of Medicine, New York, NY 10016, USA of Cell Biology, New York University, School of Medicine, New York, NY 10016, USA *Correspondence: [email protected] (D.G.), [email protected] (M.I.) https://doi.org/10.1016/j.stem.2019.11.009 2Department
Hair follicle stem cells may themselves regulate the niche environment for hair follicle regrowth. A recent Science paper from Elaine Fuchs and colleagues (Gur-Cohen et al., 2019) suggests that this involves regulation of the lymphatic system and may have implications in understanding tissue regeneration. Hair follicles (HFs) undergo rounds of regeneration throughout the life of the individual. Each regenerative cycle includes distinct phases, namely, degeneration of the lower follicle (catagen), followed by a quiescent period (telogen), and then regrowth (anagen) to yield a new lower follicle replete with new hair shaft. Stem cells (SCs) located within a specialized region in the upper follicle, the bulge, fuel this regenerative process. It is believed that the environment around these cells, termed the niche, supports
their maintenance, i.e., their dual capacity for self-renewal and differentiation (Myung and Ito, 2012). Gur-Cohen et al. (2019) report the important finding that not only does lymphatic vasculature adjacent to the telogen bulge provide essential support for HFSC quiescence, but also that activated HFSCs cyclically remodel the lymphatics to promote anagen onset leading to hair regeneration (Figure 1). That SCs may contribute to the establishment of their vascular niche has previ-
ously been explored in hematopoietic stem cell (HSC) development and maintenance within the bone marrow (Morrison and Scadden, 2014; Boulais and Frenette, 2015). It is known that vasculature, including perivascular and endothelial cells, contributes to HSC self-renewal for homeostatic and regenerative hematopoiesis. Intriguingly, HSCs may play a role in shaping this vascular niche during development. Takakura et al. (2000) found that AML1-deficient embryos that completely lack HSCs also exhibit defective
Cell Stem Cell 25, December 5, 2019 ª 2019 Elsevier Inc. 733