Osteoblastic N-cadherin is Not Required for Microenvironmental Support and Regulation of Hematopoietic Stem and Progenitor Cells

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2012 May 19

PMID 22596259

Citations 44

Authors

Olga Bromberg

Benjamin J Frisch

Jonathan M Weber

Rebecca L Porter

Roberto Civitelli

Laura M Calvi

Affiliations

Soon will be listed here.

Abstract

Hematopoietic stem cell (HSC) regulation is highly dependent on interactions with the marrow microenvironment. Controversy exists on N-cadherin's role in support of HSCs. Specifically, it is unknown whether microenvironmental N-cadherin is required for normal marrow microarchitecture and for hematopoiesis. To determine whether osteoblastic N-cadherin is required for HSC regulation, we used a genetic murine model in which deletion of Cdh2, the gene encoding N-cadherin, has been targeted to cells of the osteoblastic lineage. Targeted deletion of N-cadherin resulted in an age-dependent bone phenotype, ultimately characterized by decreased mineralized bone, but no difference in steady-state HSC numbers or function at any time tested, and normal recovery from myeloablative injury. Intermittent parathyroid hormone (PTH) treatment is well established as anabolic to bone and to increase marrow HSCs through microenvironmental interactions. Lack of osteoblastic N-cadherin did not block the bone anabolic or the HSC effects of PTH treatment. This report demonstrates that osteoblastic N-cadherin is not required for regulation of steady-state hematopoiesis, HSC response to myeloablation, or for rapid expansion of HSCs through intermittent treatment with PTH.

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References

Calvi L, Adams G, Weibrecht K, Weber J, Olson D, Knight M . Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003; 425(6960):841-6. DOI: 10.1038/nature02040. View

Kiel M, Acar M, Radice G, Morrison S . Hematopoietic stem cells do not depend on N-cadherin to regulate their maintenance. Cell Stem Cell. 2009; 4(2):170-9. PMC: 2681089. DOI: 10.1016/j.stem.2008.10.005. View

Goltzman D . Studies on the mechanisms of the skeletal anabolic action of endogenous and exogenous parathyroid hormone. Arch Biochem Biophys. 2008; 473(2):218-24. DOI: 10.1016/j.abb.2008.03.003. View

Frisch B, Ashton J, Xing L, Becker M, Jordan C, Calvi L . Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood. 2011; 119(2):540-50. PMC: 3384480. DOI: 10.1182/blood-2011-04-348151. View

Frisch B, Porter R, Gigliotti B, Olm-Shipman A, Weber J, OKeefe R . In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells. Blood. 2009; 114(19):4054-63. PMC: 2774547. DOI: 10.1182/blood-2009-03-205823. View

Mendez-Ferrer S, Michurina T, Ferraro F, Mazloom A, MacArthur B, Lira S . Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010; 466(7308):829-34. PMC: 3146551. DOI: 10.1038/nature09262. View

Kawaguchi J, Kii I, Sugiyama Y, Takeshita S, Kudo A . The transition of cadherin expression in osteoblast differentiation from mesenchymal cells: consistent expression of cadherin-11 in osteoblast lineage. J Bone Miner Res. 2001; 16(2):260-9. DOI: 10.1359/jbmr.2001.16.2.260. View

Li P, Zon L . Resolving the controversy about N-cadherin and hematopoietic stem cells. Cell Stem Cell. 2010; 6(3):199-202. DOI: 10.1016/j.stem.2010.02.007. View

Song X, Zhu C, Doan C, Xie T . Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science. 2002; 296(5574):1855-7. DOI: 10.1126/science.1069871. View

10.

Xu G, Arregui C, Lilien J, Balsamo J . PTP1B modulates the association of beta-catenin with N-cadherin through binding to an adjacent and partially overlapping target site. J Biol Chem. 2002; 277(51):49989-97. DOI: 10.1074/jbc.M206454200. View

11.

Lai C, Cheng S, Mbalaviele G, Donsante C, Watkins M, Radice G . Accentuated ovariectomy-induced bone loss and altered osteogenesis in heterozygous N-cadherin null mice. J Bone Miner Res. 2006; 21(12):1897-906. DOI: 10.1359/jbmr.060906. View

12.

Wilson A, Murphy M, Oskarsson T, Kaloulis K, Bettess M, Oser G . c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004; 18(22):2747-63. PMC: 528895. DOI: 10.1101/gad.313104. View

13.

Millard S, Louie A, Wattanachanya L, Wronski T, Conklin B, Nissenson R . Blockade of receptor-activated G(i) signaling in osteoblasts in vivo leads to site-specific increases in cortical and cancellous bone formation. J Bone Miner Res. 2010; 26(4):822-32. PMC: 3179326. DOI: 10.1002/jbmr.273. View

14.

Di Benedetto A, Watkins M, Grimston S, Salazar V, Donsante C, Mbalaviele G . N-cadherin and cadherin 11 modulate postnatal bone growth and osteoblast differentiation by distinct mechanisms. J Cell Sci. 2010; 123(Pt 15):2640-8. PMC: 2908051. DOI: 10.1242/jcs.067777. View

15.

Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari V, Patel V . Induced deletion of the N-cadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res. 2005; 96(3):346-54. DOI: 10.1161/01.RES.0000156274.72390.2c. View

16.

Essers M, Offner S, Blanco-Bose W, Waibler Z, Kalinke U, Duchosal M . IFNalpha activates dormant haematopoietic stem cells in vivo. Nature. 2009; 458(7240):904-8. DOI: 10.1038/nature07815. View

17.

Kawaguchi J, Azuma Y, Hoshi K, Kii I, Takeshita S, Ohta T . Targeted disruption of cadherin-11 leads to a reduction in bone density in calvaria and long bone metaphyses. J Bone Miner Res. 2001; 16(7):1265-71. DOI: 10.1359/jbmr.2001.16.7.1265. View

18.

Zhang J, Niu C, Ye L, Huang H, He X, Tong W . Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003; 425(6960):836-41. DOI: 10.1038/nature02041. View

19.

Kuhn R, Schwenk F, Aguet M, Rajewsky K . Inducible gene targeting in mice. Science. 1995; 269(5229):1427-9. DOI: 10.1126/science.7660125. View

20.

Visnjic D, Kalajzic Z, Rowe D, Katavic V, Lorenzo J, Aguila H . Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood. 2004; 103(9):3258-64. DOI: 10.1182/blood-2003-11-4011. View