1. ¹Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York, USA
2. ²Laboratory for Soft Tissue Research, The Hospital for Special Surgery, New York, New York, USA

Correspondence: Ronald G Crystal, Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, New York 10065, USA. E-mail: geneticmedicine@med.cornell.edu

Received 28 July 2008; Accepted 3 April 2009; Published online 12 May 2009.

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.