Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis

Marta B. Alvarez, Lin Lin Xu, Paul J. Childress, Kevin A. Maupin, Safa F. Mohamad, Brahmananda R. Chitteti, Evan Himes, David J. Olivos, Ying Hua Cheng, Simon Conway, Edward Srour, Melissa Kacena

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Emerging evidence demonstrates that megakaryocytes (MK) play key roles in regulating skeletal homeostasis and hematopoiesis. To test if the loss of MK negatively impacts osteoblastogenesis and hematopoiesis, we generated conditional knockout mice where Mpl, the receptor for the main MK growth factor, thrombopoietin, was deleted specifically in MK (Mplf/f;PF4cre). Unexpectedly, at 12 weeks of age, these mice exhibited a 10-fold increase in platelets, a significant expansion of hematopoietic/mesenchymal precursors, and a remarkable 20-fold increase in femoral midshaft bone volume. We then investigated whether MK support hematopoietic stem cell (HSC) function through the interaction of MK with osteoblasts (OB). LSK cells (Lin-Sca1+CD117+, enriched HSC population) were co-cultured with OB+MK for 1 week (1wk OB+MK+LSK) or OB alone (1wk OB+LSK). A significant increase in colony-forming units was observed with cells from 1wk OB+MK cultures. Competitive repopulation studies demonstrated significantly higher engraftment in mice transplanted with cells from 1wk OB+MK+LSK cultures compared to 1wk OB+LSK or LSK cultured alone for 1 week. Furthermore, single-cell expression analysis of OB cultured±MK revealed adiponectin as the most significantly upregulated MK-induced gene, which is required for optimal long-term hematopoietic reconstitution. Understanding the interactions between MK, OB, and HSC can inform the development of novel treatments to enhance both HSC recovery following myelosuppressive injuries, as well as bone loss diseases, such as osteoporosis.

Original languageEnglish (US)
Pages (from-to)671-682
Number of pages12
JournalStem Cells and Development
Volume27
Issue number10
DOIs
StatePublished - May 15 2018

Fingerprint

Megakaryocytes
Hematopoiesis
Osteoblasts
Bone and Bones
Hematopoietic Stem Cells
Single-Cell Analysis
Thrombopoietin
Bone Diseases
Adiponectin
Thigh
Knockout Mice
Osteoporosis
Intercellular Signaling Peptides and Proteins
Homeostasis
Stem Cells
Blood Platelets

Keywords

  • bone regeneration
  • hematopoiesis
  • hematopoietic stem cells
  • megakaryocytes
  • osteoblasts

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

Cite this

Alvarez, M. B., Xu, L. L., Childress, P. J., Maupin, K. A., Mohamad, S. F., Chitteti, B. R., ... Kacena, M. (2018). Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis. Stem Cells and Development, 27(10), 671-682. https://doi.org/10.1089/scd.2017.0178

Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis. / Alvarez, Marta B.; Xu, Lin Lin; Childress, Paul J.; Maupin, Kevin A.; Mohamad, Safa F.; Chitteti, Brahmananda R.; Himes, Evan; Olivos, David J.; Cheng, Ying Hua; Conway, Simon; Srour, Edward; Kacena, Melissa.

In: Stem Cells and Development, Vol. 27, No. 10, 15.05.2018, p. 671-682.

Research output: Contribution to journalArticle

Alvarez, MB, Xu, LL, Childress, PJ, Maupin, KA, Mohamad, SF, Chitteti, BR, Himes, E, Olivos, DJ, Cheng, YH, Conway, S, Srour, E & Kacena, M 2018, 'Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis', Stem Cells and Development, vol. 27, no. 10, pp. 671-682. https://doi.org/10.1089/scd.2017.0178
Alvarez MB, Xu LL, Childress PJ, Maupin KA, Mohamad SF, Chitteti BR et al. Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis. Stem Cells and Development. 2018 May 15;27(10):671-682. https://doi.org/10.1089/scd.2017.0178
Alvarez, Marta B. ; Xu, Lin Lin ; Childress, Paul J. ; Maupin, Kevin A. ; Mohamad, Safa F. ; Chitteti, Brahmananda R. ; Himes, Evan ; Olivos, David J. ; Cheng, Ying Hua ; Conway, Simon ; Srour, Edward ; Kacena, Melissa. / Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis. In: Stem Cells and Development. 2018 ; Vol. 27, No. 10. pp. 671-682.
@article{6699f8af835b49e3bac902d4b9b03177,
title = "Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis",
abstract = "Emerging evidence demonstrates that megakaryocytes (MK) play key roles in regulating skeletal homeostasis and hematopoiesis. To test if the loss of MK negatively impacts osteoblastogenesis and hematopoiesis, we generated conditional knockout mice where Mpl, the receptor for the main MK growth factor, thrombopoietin, was deleted specifically in MK (Mplf/f;PF4cre). Unexpectedly, at 12 weeks of age, these mice exhibited a 10-fold increase in platelets, a significant expansion of hematopoietic/mesenchymal precursors, and a remarkable 20-fold increase in femoral midshaft bone volume. We then investigated whether MK support hematopoietic stem cell (HSC) function through the interaction of MK with osteoblasts (OB). LSK cells (Lin-Sca1+CD117+, enriched HSC population) were co-cultured with OB+MK for 1 week (1wk OB+MK+LSK) or OB alone (1wk OB+LSK). A significant increase in colony-forming units was observed with cells from 1wk OB+MK cultures. Competitive repopulation studies demonstrated significantly higher engraftment in mice transplanted with cells from 1wk OB+MK+LSK cultures compared to 1wk OB+LSK or LSK cultured alone for 1 week. Furthermore, single-cell expression analysis of OB cultured±MK revealed adiponectin as the most significantly upregulated MK-induced gene, which is required for optimal long-term hematopoietic reconstitution. Understanding the interactions between MK, OB, and HSC can inform the development of novel treatments to enhance both HSC recovery following myelosuppressive injuries, as well as bone loss diseases, such as osteoporosis.",
keywords = "bone regeneration, hematopoiesis, hematopoietic stem cells, megakaryocytes, osteoblasts",
author = "Alvarez, {Marta B.} and Xu, {Lin Lin} and Childress, {Paul J.} and Maupin, {Kevin A.} and Mohamad, {Safa F.} and Chitteti, {Brahmananda R.} and Evan Himes and Olivos, {David J.} and Cheng, {Ying Hua} and Simon Conway and Edward Srour and Melissa Kacena",
year = "2018",
month = "5",
day = "15",
doi = "10.1089/scd.2017.0178",
language = "English (US)",
volume = "27",
pages = "671--682",
journal = "Stem Cells and Development",
issn = "1547-3287",
publisher = "Mary Ann Liebert Inc.",
number = "10",

}

TY - JOUR

T1 - Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis

AU - Alvarez, Marta B.

AU - Xu, Lin Lin

AU - Childress, Paul J.

AU - Maupin, Kevin A.

AU - Mohamad, Safa F.

AU - Chitteti, Brahmananda R.

AU - Himes, Evan

AU - Olivos, David J.

AU - Cheng, Ying Hua

AU - Conway, Simon

AU - Srour, Edward

AU - Kacena, Melissa

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Emerging evidence demonstrates that megakaryocytes (MK) play key roles in regulating skeletal homeostasis and hematopoiesis. To test if the loss of MK negatively impacts osteoblastogenesis and hematopoiesis, we generated conditional knockout mice where Mpl, the receptor for the main MK growth factor, thrombopoietin, was deleted specifically in MK (Mplf/f;PF4cre). Unexpectedly, at 12 weeks of age, these mice exhibited a 10-fold increase in platelets, a significant expansion of hematopoietic/mesenchymal precursors, and a remarkable 20-fold increase in femoral midshaft bone volume. We then investigated whether MK support hematopoietic stem cell (HSC) function through the interaction of MK with osteoblasts (OB). LSK cells (Lin-Sca1+CD117+, enriched HSC population) were co-cultured with OB+MK for 1 week (1wk OB+MK+LSK) or OB alone (1wk OB+LSK). A significant increase in colony-forming units was observed with cells from 1wk OB+MK cultures. Competitive repopulation studies demonstrated significantly higher engraftment in mice transplanted with cells from 1wk OB+MK+LSK cultures compared to 1wk OB+LSK or LSK cultured alone for 1 week. Furthermore, single-cell expression analysis of OB cultured±MK revealed adiponectin as the most significantly upregulated MK-induced gene, which is required for optimal long-term hematopoietic reconstitution. Understanding the interactions between MK, OB, and HSC can inform the development of novel treatments to enhance both HSC recovery following myelosuppressive injuries, as well as bone loss diseases, such as osteoporosis.

AB - Emerging evidence demonstrates that megakaryocytes (MK) play key roles in regulating skeletal homeostasis and hematopoiesis. To test if the loss of MK negatively impacts osteoblastogenesis and hematopoiesis, we generated conditional knockout mice where Mpl, the receptor for the main MK growth factor, thrombopoietin, was deleted specifically in MK (Mplf/f;PF4cre). Unexpectedly, at 12 weeks of age, these mice exhibited a 10-fold increase in platelets, a significant expansion of hematopoietic/mesenchymal precursors, and a remarkable 20-fold increase in femoral midshaft bone volume. We then investigated whether MK support hematopoietic stem cell (HSC) function through the interaction of MK with osteoblasts (OB). LSK cells (Lin-Sca1+CD117+, enriched HSC population) were co-cultured with OB+MK for 1 week (1wk OB+MK+LSK) or OB alone (1wk OB+LSK). A significant increase in colony-forming units was observed with cells from 1wk OB+MK cultures. Competitive repopulation studies demonstrated significantly higher engraftment in mice transplanted with cells from 1wk OB+MK+LSK cultures compared to 1wk OB+LSK or LSK cultured alone for 1 week. Furthermore, single-cell expression analysis of OB cultured±MK revealed adiponectin as the most significantly upregulated MK-induced gene, which is required for optimal long-term hematopoietic reconstitution. Understanding the interactions between MK, OB, and HSC can inform the development of novel treatments to enhance both HSC recovery following myelosuppressive injuries, as well as bone loss diseases, such as osteoporosis.

KW - bone regeneration

KW - hematopoiesis

KW - hematopoietic stem cells

KW - megakaryocytes

KW - osteoblasts

UR - http://www.scopus.com/inward/record.url?scp=85047565765&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85047565765&partnerID=8YFLogxK

U2 - 10.1089/scd.2017.0178

DO - 10.1089/scd.2017.0178

M3 - Article

C2 - 29631496

AN - SCOPUS:85047565765

VL - 27

SP - 671

EP - 682

JO - Stem Cells and Development

JF - Stem Cells and Development

SN - 1547-3287

IS - 10

ER -