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NDT Advance Access originally published online on May 15, 2006
Nephrology Dialysis Transplantation 2006 21(8):2072-2074; doi:10.1093/ndt/gfl206
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Translational Nephrology

Haematopoietic stem cells—role of calcium-sensing receptor in bone marrow homing*

Tilman Bernhard Drüeke

Inserm Unit 507 and Service de Néphrologie, Hôpital Necker, Paris, France

Correspondence and offprint requests to: Tilman B. Drüeke, MD, FRCP, Unité 507 de l'Inserm and Service de Néphrologie, Hôpital Necker, 161 rue de Sèvres, 75743 Paris Cedex 15, France. Email: drueke{at}necker.fr

Keywords: bone; calcium-sensing receptor; erythropoiesis; haematopoiesis; liver; stem cells

Erythropoiesis switches from liver to bone around the time of birth [1], hepatic erythropoietin production is progressively replaced by renal erythropoietin production [2] and fetal haemoglobin gives way to adult haemoglobin [3]. The mechanisms involved in these translocations and changes remain largely a mystery. After birth, the haematopoietic stem cells (HSCs) migrate via the circulation to specific sites in the bone marrow (Figure 1). These are cavities at the endosteal surface of the bone called ‘stem cell niche’ [4,5]. Notably, transplanted HSCs lodge at the endosteal niche within hours of intravenous injection [6].


Figure 1
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  		Fig. 1. Schematic view of the neonatal switch of haematopoiesis from liver to bone and the role of the CaR. Normal CaR expression (CaR+/+) on primitive HSCs is an absolute requirement for HSC lodging in the endosteal niche of the bone marrow. CaR deficient (CaR–/–) HSCs are unable to adhere to endosteal osteoblasts, SSCs and collagen I and to engage into local proliferation and maturation.

 
A question which has received much attention in recent years is, which factors are involved in HSC homing at a specific site. The first candidate was the osteoblast, since it is anatomically close and since it produces many factors essential to the survival, renewal and maturation of HSCs, including the colony-stimulating growth factors granulocyte-colony-stimulating factor (G-CSF), macrophage-colony-stimulating factor (M-CSF) and granulocyte/macrophage-colony-stimulating factor (GM-CSF), numerous other growth factors such as as interleukin-1-beta (IL-1b), interleukin-6 (IL-6), interleukin-7 (IL-7), osteoprotegerin, receptor activator of NF-kappa-B ligand (RANKL), stromal-derived factor-1, tumour-necrosis factor-{alpha} (TNF-{alpha}) and vascular endothelial growth factor (VEGF) [5]. Additional support for a major role of the osteoblast came from two recent reports. They showed that bone morphogenic protein signalling pathway is involved in adult HSC development [7], and that angiopoietin-1 produced by osteoblasts activates the stem cell receptor tyrosine kinase Tie2 and thereby promotes tight adhesion of stem cells to their niche [8]. These and other observations strongly suggest that osteogenesis and haematopoiesis are functionally linked. The second major candidate is the stroma which provides appropriate environmental cues for haematopoiesis [9]. The stroma is composed of a variety of stromal stem cells (SSCs), which are mostly derived from the same lineage as cartilage and bone cells, including fibroblasts, macrophages, endothelial cells and adipocytes. Finally, extracellular matrix proteins such as collagen and glycosamines, and adhesion molecules such as very late antigen-4 (VLA-4), very late antigen-5 (VLA-5), fibronectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) also play a role [5].

Specific links also exist between haematopoiesis and factors involved in bone and mineral metabolism which are better known to nephrologists. Thus parathyroid hormone (PTH), via the parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrp) receptor, is a major regulator of the ontogeny of the bone marrow and its stromal tissue. PTH injection into mice increases HSC number [9,10]. Osteopontin is a negative regulatory element of the stem cell niche [11].

In the search for additional links with calcium metabolism, Adams et al. [12] reasoned that the extremely high calcium concentrations observed at the endosteal sites near resorbing osteoclasts—up to 40 mmol/l—could exert specific effects on local stem cells via the calcium-sensing receptor (CaR). Since it was known that CaR is also expressed on haematopoietic cells, including cells of the monocyte/macrophage lineage [13], their idea clearly had a certain merit. They reasoned further that if expressed on HSCs, CaR might affect stem cell responses to the unique endosteal microenvironment. This is exactly what they found. To prove their hypothesis, they used one of our best friends in laboratory research, the mouse. They made mice deficient in CaR (CaR–/–) by a common gene knock-out technique.

First of all, in examining CaR–/– mice before birth, they found that the animals had abundant primitive haematopoietic cells in the circulation and the spleen, but few in the bone marrow. CaR–/– HSCs in fetal liver were normal in number. Their proliferation and differentiation were also normal.

Second, when counting the frequency of haematopoietic progenitor cells relative to other bone marrow cell types, namely T-cells, B-cells, granulocytes and monocytes, they found that the observed bone marrow hypocellularity was exclusively due to a reduction in the number of haematopoietic cells.

Third, on closer scrutiny concerning the migration from liver to bone, CaR–/– HSCs had no problem in reaching the bone marrow and homing there. However, at this point they encountered an obstacle. They failed to lodge in the endosteal niche. The authors then tried to identify the mechanism or mechanisms responsible for this disability. They looked for possible defects in the expression or activity of a variety of cell surface molecules, but could not incriminate any of them. Using elegant HSC transplantation experiments into lethally irradiated wild-type mice, they found that the failure to lodge was not secondary to CaR–/– deficiency of the host bone marrow cells, but to CaR–/– deficiency of the HSCs.

Fourth, the authors assessed in a very detailed manner the adherence process of primitive HSCs to substrates present in the bone marrow microenvironment. They found a specific defect in the ability of CaR–/– HSCs to adhere to collagen I, the most prominent extracellular matrix protein of bone produced by osteoblasts.

The authors concluded that the absence of a functional CaR induced an autonomous defect in the primitive HSCs, preventing them from lodging in the endosteal niche. These stem cells thus resemble nomads, who are unwilling or unable to adopt a sedentary state. The authors also made the hypothesis that the CaR–/– HSCs preferentially localize near cells releasing calcium into the extracellular space, the osteoclasts, rather than the osteoblasts. Since osteoblasts and osteoclasts form a functional bone remodelling unit, it is possible that the local ionized calcium concentration directly alters the HSC function through the CaR, and indirectly through the known effects of calcium on local adhesion processes.

Figure 1 provides a schematic view of endosteal HSC homing after birth and CaR's proposed implication in this process.

What are the implications of the aforesaid findings for the clinician? First of all, they are a significant step forward in our understanding of the neonatal switch of erythropoiesis from liver to bone. Whereas the cartilaginous structure of fetal bone does not fulfil the requirements of a haematopoietic marrow, in particular the set-up of an endosteal niche, the calcifying structure of post-natal bone does. The presence of high local calcium concentrations may be one of the requirements. Second, conditions or agents capable of modulating CaR expression or function might alter the efficiency of erythropoiesis. Thus secondary hyperparathyroidism [14,15] and changes in phosphate intake [16], both known to modify CaR expression, or the administration of calcimimetics or calcilytics [17,18] for clinical purposes could alter HSC homing or function and ultimately red blood cell production. However, to the best of our knowledge, no direct or indirect beneficial effect of calcimimetics on anaemia in chronic kidney disease patients has been reported so far. It would be interesting to examine this possibility in future studies. Finally, in human stem cell transplantation, the modulation of CaR function with drugs could represent a strategy to either enhance or stabilize the engraftment of transplanted HSCs in the endosteal niche or, conversely, to mobilize stem cells from it [12].

Conflict of interest statement. TD received lecture fees, consulting fees and grant support from Amgen, and consulting fees from Hoffmann-La Roche.



   Notes
 
*Comment on Adams GB, Chabner KT, Alley IR et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 2006; 439: 599–603 Back



   References
Top
 References
 

  1. Tavassoli M. Embryonic and fetal hemopoiesis: an overview. Blood Cells 1991; 17: 269–281[ISI][Medline]
  2. Eckardt KU, Ratcliffe PJ, Tan CC, Bauer C, Kurtz A. Age-dependent expression of the erythropoietin gene in rat liver and kidneys. J Clin Invest 1992; 89: 753–760[ISI][Medline]
  3. Weinberg RS, Goldberg JD, Schofield JM, Lenes AL, Styczynski R, Alter BP. Switch from fetal to adult hemoglobin is associated with a change in progenitor cell population. J Clin Invest 1983; 71: 785–794[ISI][Medline]
  4. Haylock DN, Nilsson SK. Stem cell regulation by the hematopoietic stem cell niche. Cell Cycle 2005; 4: 1353–1355[ISI][Medline]
  5. Taichman RS. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood 2005; 105: 2631–2639[Abstract/Free Full Text]
  6. Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 2001; 97: 2293–2299[Abstract/Free Full Text]
  7. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 2003; 425: 836–841[CrossRef][Medline]
  8. Arai F, Hirao A, Ohmura M, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 2004; 118: 149–161[CrossRef][ISI][Medline]
  9. Kuznetsov SA, Riminucci M, Ziran N, et al. The interplay of osteogenesis and hematopoiesis: expression of a constitutively active PTH/PTHrP receptor in osteogenic cells perturbs the establishment of hematopoiesis in bone and of skeletal stem cells in the bone marrow. J Cell Biol 2004; 167: 1113–1122[Abstract/Free Full Text]
  10. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 2003; 425: 841–846[CrossRef][Medline]
  11. Stier S, Ko Y, Forkert R, et al. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J Exp Med 2005; 201: 1781–1791[Abstract/Free Full Text]
  12. Adams GB, Chabner KT, Alley IR, et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 2006; 439: 599–603[CrossRef][Medline]
  13. House MG, Kohlmeier L, Chattopadhyay N, et al. Expression of an extracellular calcium-sensing receptor in human and mouse bone marrow cells. J Bone Miner Res 1997; 12: 1959–1970[CrossRef][ISI][Medline]
  14. Drueke TB, Eckardt KU. Role of secondary hyperparathyroidism in erythropoietin resistance of chronic renal failure patients. Nephrol Dial Transplant 2002; 17: 28–31[Abstract/Free Full Text]
  15. Gogusev J, Duchambon P, Hory B, Giovannini M, Sarfati E, Drüeke TB. Depressed expression of calcium receptor in parathyroid gland tissue of patients with primary or secondary uremic hyperparathyroidism. Kidney Int 1997; 51: 328–336[ISI][Medline]
  16. Brown AJ, Ritter CS, Finch JL, Slatopolsky EA. Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate. Kidney Int 1999; 55: 1284–1292[CrossRef][ISI][Medline]
  17. Hebert SC. Therapeutic use of calcimimetics. Annu Rev Med 2006; 57: 349–364[CrossRef][ISI][Medline]
  18. Steddon S, Cunningham J. Calcimimetics and calcilytics – fooling the calcium receptor. Lancet 2005; 365: 2237–2239[CrossRef][ISI][Medline]
Received for publication: 28. 2.06
Accepted in revised form: 22. 3.06


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