Trophoblasts Regulate the Placental Hematopoietic Niche through PDGF-B Signaling

Akanksha Chhabra; Andrew J. Lechner; Masaya Ueno; Asha Acharya; Ben Van Handel; Yanling Wang; M. Luisa Iruela-Arispe; Michelle D. Tallquist; Hanna K A Mikkola

doi:10.1016/j.devcel.2011.12.022

Trophoblasts Regulate the Placental Hematopoietic Niche through PDGF-B Signaling

Akanksha Chhabra, Andrew J. Lechner, Masaya Ueno, Asha Acharya, Ben Van Handel, Yanling Wang, M. Luisa Iruela-Arispe, Michelle D. Tallquist, Hanna K A Mikkola

Molecular Biology

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43 Scopus citations

Abstract

The placenta is a hematopoietic organ that supports hematopoietic stem/progenitor cell (HSPC) generation and expansion without promoting differentiation. We identified PDGF-B signaling in trophoblasts as a key component of the unique placental hematopoietic microenvironment that protects HSPCs from premature differentiation. Loss of PDGF-B or its receptor, PDGFRβ, induced definitive erythropoiesis in placental labyrinth vasculature. This was evidenced by accumulation of CFU-Es and actively proliferating definitive erythroblasts that clustered around central macrophages, highly reminiscent of erythropoiesis in the fetal liver. Ectopic erythropoiesis was not due to a requirement of PDGF-B signaling in hematopoietic cells but rather in placental trophoblasts, which upregulated Epo in the absence of PDGF-B signaling. Furthermore, overexpression of hEPO specifically in the trophoblasts in vivo was sufficient to convert the placenta into an erythropoietic organ. These data provide genetic evidence of a signaling pathway that is required to restrict erythroid differentiation to specific anatomical niches during development. Video Abstract: The placenta is an important embryonic niche for hematopoietic stem/progenitor cells (HSPCs). Chhabra et al. find that PDGF signaling suppresses Epo production by placental trophoblasts and thereby attenuates placental erythropoiesis. Thus, PDGF signaling determines niche characteristics that in turn influence resident HSPCs to control the cell-type specificity of HSPC output.

Original language	English (US)
Pages (from-to)	651-659
Number of pages	9
Journal	Developmental cell
Volume	22
Issue number	3
DOIs	https://doi.org/10.1016/j.devcel.2011.12.022
State	Published - Mar 13 2012

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2011.12.022

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title = "Trophoblasts Regulate the Placental Hematopoietic Niche through PDGF-B Signaling",

abstract = "The placenta is a hematopoietic organ that supports hematopoietic stem/progenitor cell (HSPC) generation and expansion without promoting differentiation. We identified PDGF-B signaling in trophoblasts as a key component of the unique placental hematopoietic microenvironment that protects HSPCs from premature differentiation. Loss of PDGF-B or its receptor, PDGFRβ, induced definitive erythropoiesis in placental labyrinth vasculature. This was evidenced by accumulation of CFU-Es and actively proliferating definitive erythroblasts that clustered around central macrophages, highly reminiscent of erythropoiesis in the fetal liver. Ectopic erythropoiesis was not due to a requirement of PDGF-B signaling in hematopoietic cells but rather in placental trophoblasts, which upregulated Epo in the absence of PDGF-B signaling. Furthermore, overexpression of hEPO specifically in the trophoblasts in vivo was sufficient to convert the placenta into an erythropoietic organ. These data provide genetic evidence of a signaling pathway that is required to restrict erythroid differentiation to specific anatomical niches during development. Video Abstract: The placenta is an important embryonic niche for hematopoietic stem/progenitor cells (HSPCs). Chhabra et al. find that PDGF signaling suppresses Epo production by placental trophoblasts and thereby attenuates placental erythropoiesis. Thus, PDGF signaling determines niche characteristics that in turn influence resident HSPCs to control the cell-type specificity of HSPC output.",

author = "Akanksha Chhabra and Lechner, {Andrew J.} and Masaya Ueno and Asha Acharya and {Van Handel}, Ben and Yanling Wang and Iruela-Arispe, {M. Luisa} and Tallquist, {Michelle D.} and Mikkola, {Hanna K A}",

note = "Funding Information: We thank Christer Betsholtz for Pdgf-b +/− mice, Hong Wu for sharing unpublished data, and James Palis and Paul Kingsley for anti-βH1 globin antibody. We thank Andrew Goldstein for virus preparation and critical reading of the manuscript and Janet Treger at the UCLA Virology Core for virus preparation. We thank the UCLA Translational Pathology Core Laboratory for preparing paraffin sections, Marianne Cilluffo at the UCLA Electron Microscopy Laboratory for electron microscopy, Ying Wang and Meisheng Jiang at Molecular and Medical Pharmacology Department for trophoblast-specific gene targeting, and the UCLA Division of Laboratory Animal Medicine for blood analysis. This work was supported by an NIH RO1 HL097766-01 and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA Innovation Award to H.K.A.M. and NIH RO1 HL074257 to M.D.T. A.C. was supported by predoctoral training grants from California Institute for Regenerative Medicine (T1-00005 and TG2-01169) and Jonsson Comprehensive Cancer Center Foundation at UCLA. A.J.L. was supported by the Howard Hughes Undergraduate Research Program. M.U. was supported by The Japan Society for the Promotion of Science. B.V.H. was supported by the Ruth L. Kirschstein National Research Service Award GM007185 and NIH/NHLBI T32 HL69766. ",

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AU - Chhabra, Akanksha

AU - Lechner, Andrew J.

AU - Ueno, Masaya

AU - Acharya, Asha

AU - Van Handel, Ben

AU - Wang, Yanling

AU - Iruela-Arispe, M. Luisa

AU - Tallquist, Michelle D.

AU - Mikkola, Hanna K A

N1 - Funding Information: We thank Christer Betsholtz for Pdgf-b +/− mice, Hong Wu for sharing unpublished data, and James Palis and Paul Kingsley for anti-βH1 globin antibody. We thank Andrew Goldstein for virus preparation and critical reading of the manuscript and Janet Treger at the UCLA Virology Core for virus preparation. We thank the UCLA Translational Pathology Core Laboratory for preparing paraffin sections, Marianne Cilluffo at the UCLA Electron Microscopy Laboratory for electron microscopy, Ying Wang and Meisheng Jiang at Molecular and Medical Pharmacology Department for trophoblast-specific gene targeting, and the UCLA Division of Laboratory Animal Medicine for blood analysis. This work was supported by an NIH RO1 HL097766-01 and Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA Innovation Award to H.K.A.M. and NIH RO1 HL074257 to M.D.T. A.C. was supported by predoctoral training grants from California Institute for Regenerative Medicine (T1-00005 and TG2-01169) and Jonsson Comprehensive Cancer Center Foundation at UCLA. A.J.L. was supported by the Howard Hughes Undergraduate Research Program. M.U. was supported by The Japan Society for the Promotion of Science. B.V.H. was supported by the Ruth L. Kirschstein National Research Service Award GM007185 and NIH/NHLBI T32 HL69766.

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N2 - The placenta is a hematopoietic organ that supports hematopoietic stem/progenitor cell (HSPC) generation and expansion without promoting differentiation. We identified PDGF-B signaling in trophoblasts as a key component of the unique placental hematopoietic microenvironment that protects HSPCs from premature differentiation. Loss of PDGF-B or its receptor, PDGFRβ, induced definitive erythropoiesis in placental labyrinth vasculature. This was evidenced by accumulation of CFU-Es and actively proliferating definitive erythroblasts that clustered around central macrophages, highly reminiscent of erythropoiesis in the fetal liver. Ectopic erythropoiesis was not due to a requirement of PDGF-B signaling in hematopoietic cells but rather in placental trophoblasts, which upregulated Epo in the absence of PDGF-B signaling. Furthermore, overexpression of hEPO specifically in the trophoblasts in vivo was sufficient to convert the placenta into an erythropoietic organ. These data provide genetic evidence of a signaling pathway that is required to restrict erythroid differentiation to specific anatomical niches during development. Video Abstract: The placenta is an important embryonic niche for hematopoietic stem/progenitor cells (HSPCs). Chhabra et al. find that PDGF signaling suppresses Epo production by placental trophoblasts and thereby attenuates placental erythropoiesis. Thus, PDGF signaling determines niche characteristics that in turn influence resident HSPCs to control the cell-type specificity of HSPC output.

AB - The placenta is a hematopoietic organ that supports hematopoietic stem/progenitor cell (HSPC) generation and expansion without promoting differentiation. We identified PDGF-B signaling in trophoblasts as a key component of the unique placental hematopoietic microenvironment that protects HSPCs from premature differentiation. Loss of PDGF-B or its receptor, PDGFRβ, induced definitive erythropoiesis in placental labyrinth vasculature. This was evidenced by accumulation of CFU-Es and actively proliferating definitive erythroblasts that clustered around central macrophages, highly reminiscent of erythropoiesis in the fetal liver. Ectopic erythropoiesis was not due to a requirement of PDGF-B signaling in hematopoietic cells but rather in placental trophoblasts, which upregulated Epo in the absence of PDGF-B signaling. Furthermore, overexpression of hEPO specifically in the trophoblasts in vivo was sufficient to convert the placenta into an erythropoietic organ. These data provide genetic evidence of a signaling pathway that is required to restrict erythroid differentiation to specific anatomical niches during development. Video Abstract: The placenta is an important embryonic niche for hematopoietic stem/progenitor cells (HSPCs). Chhabra et al. find that PDGF signaling suppresses Epo production by placental trophoblasts and thereby attenuates placental erythropoiesis. Thus, PDGF signaling determines niche characteristics that in turn influence resident HSPCs to control the cell-type specificity of HSPC output.

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Trophoblasts Regulate the Placental Hematopoietic Niche through PDGF-B Signaling

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