Chronic kidney failure mineral bone disorder leads to a permanent loss of hematopoietic stem cells through dysfunction of the stem cell niche

Marina A Aleksinskaya,Harrie Weinans,Anton Jan Van Zonneveld,Ziad A Massy,Ruben G De Bruin,Melissa Van Pel,Willem E Fibbe,Michiel Siebelt,Edith M Slot,Matthieu Monge,Karin M Koekkoek,Ton J Rabelink

doi:10.1038/s41598-018-33979-7

Abstract

In chronic kidney disease (CKD), endothelial injury, is associated with disease progression and an increased risk for cardiovascular complications. Circulating cells with vascular reparative functions are hematopoietic and also reduced in CKD. To explore the mechanistic basis behind these observations, we have investigated hematopoietic stem cell (HSC) homeostasis in a mouse model for non-progressive CKD-mineral and bone disorder with experimentally induced chronic renal failure (CRF). In mice subjected to 12 weeks of CRF, bone marrow HSC frequencies were decreased and transplantation of bone marrow cells from CRF donors showed a decrease in long-term HSC repopulation compared to controls. This loss was directly associated with a CRF-induced defect in the HSC niche affecting the cell cycle status of HSC and could not be restored by the PTH-reducing agent cinacalcet. In CRF, frequencies of quiescent (G0) HSC were decreased coinciding with an increase in hematopoietic progenitor cells (HPC) in the S-and G2-phases of cell cycle. Moreover, in CRF mice, HSC-niche supporting macrophages were decreased compared to controls concomitant to impaired B lymphopoiesis. Our data point to a permanent loss of HSC and may provide insight into the root cause of the loss of homeostatic potential in CKD.

Highlights

Chronic kidney disease (CKD) is a pathophysiological condition characterized by a progressive loss of kidney function
All chronic renal failure (CRF) mice showed features typical of chronic kidney disease (CKD), consistent with earlier studies performed with this model (Table 1)[26]
As a result of CRF, bone structural changes were observed in the metaphysis region, including increased trabecular bone volume density (BV/tissue volume (TV)) and decreased trabecular structure model index (SMI) by a tendency to a more plate-like shape (Table 1, Supplementary Fig. 1)[27]

Summary

Introduction

Chronic kidney disease (CKD) is a pathophysiological condition characterized by a progressive loss of kidney function. In CKD, phosphate retention, decreased (active) vitamin D and increased fibroblast growth factor 23 concentrations are the main driving factors that lead to secondary hyperparathyroidism[1] This dysregulation of the parathyroid gland is characterized by the sustained release of parathyroid hormone (PTH) that drives bone remodeling by increasing osteoclast and osteoblast activities and bone turnover. Hematopoietic stem cells (HSC) are the only cells that have the enduring capacity to produce all blood cell lineages They possess self-renewal capacity and reside in specialized microenvironments in the BM. HSC proliferation needs to adapt to differential circumstances including steady state hematopoiesis, stress-induced self-renewing proliferation, inflammation and blood loss These processes need to be tightly regulated as uncontrolled HSC proliferation may lead to stem cell exhaustion[10,11]. CaSR-signalling increases CXCR4 signalling in HSC and increases HSC-binding to the extracellular matrix in the hematopoietic stem cell niche

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Conclusion