Sonic hedgehog expands diaphyseal trabecular bone altering bone marrow niche and lymphocyte compartment

Maija Kiuru, Chisa Hidaka, Ralf Harto Hubner, Jason Solomon, Anja Krause, Philip L. Leopold, Ronald Crystal

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Bone marrow contains distinct microenvironments that regulate hematopoietic stem cells (HSCs). The endosteal HSC niche includes osteoblasts, mineral, and extracellular matrix proteins that interact through various molecular signals to control HSCs. Sonic hedgehog (Shh) is a morphogen involved in the regulation of skeletal development and hematopoiesis, but the effects of Shh on bone in relation to the HSC niche are not well understood. We demonstrate that systemic overexpression of Shh in mice increases osteoblast number with the resultant formation of new trabeculae in the femoral diaphysis. Suggestive of a functional change in the hematopoietic niche, numbers of Lin- Sca-1+ c-Kit+ cells with hematopoietic progenitor function expand, although cells with in vivo repopulating capacity in the wild-type environment do not increase. Instead, Shh mediates a decrease in number of bone marrow lymphocytes accompanied by a decreased expression of stromal-derived growth factor 1 (SDF-1) and a decrease in Flk2-expressing Lin- Sca-1+ c-Kit+ cells, indicating a modulation of early lymphopoiesis. This is caused by a microenvironment-induced mechanism as Shh treatment of bone marrow recipients, but not donors, results in a dramatic depletion of lymphocytes. Together, these data suggest that Shh mediates alterations in the bone marrow hematopoietic niche affecting the early lymphoid differentiation.

Original languageEnglish
Pages (from-to)1442-1452
Number of pages11
JournalMolecular Therapy
Volume17
Issue number8
DOIs
Publication statusPublished - 13 May 2009
Externally publishedYes

Fingerprint

Hedgehogs
Hematopoietic Stem Cells
Bone Marrow
Lymphocytes
Bone and Bones
Stem Cell Niche
Osteoblasts
Lymphopoiesis
Lymphocyte Depletion
Diaphyses
Extracellular Matrix Proteins
Hematopoiesis
Thigh
Minerals
Cancellous Bone
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

Cite this

Sonic hedgehog expands diaphyseal trabecular bone altering bone marrow niche and lymphocyte compartment. / Kiuru, Maija; Hidaka, Chisa; Hubner, Ralf Harto; Solomon, Jason; Krause, Anja; Leopold, Philip L.; Crystal, Ronald.

In: Molecular Therapy, Vol. 17, No. 8, 13.05.2009, p. 1442-1452.

Research output: Contribution to journalArticle

Kiuru, Maija ; Hidaka, Chisa ; Hubner, Ralf Harto ; Solomon, Jason ; Krause, Anja ; Leopold, Philip L. ; Crystal, Ronald. / Sonic hedgehog expands diaphyseal trabecular bone altering bone marrow niche and lymphocyte compartment. In: Molecular Therapy. 2009 ; Vol. 17, No. 8. pp. 1442-1452.
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