Klotho deficiency disrupts hematopoietic stem cell development and erythropoiesis

Sangeetha Vadakke Madathil, Lindsay M. Coe, Carla Casu, Despina Sitara

Research output: Contribution to journalArticle

Abstract

Klotho deficiency is a characteristic feature of chronic kidney disease in which anemia and cardiovascular complications are prevalent. Disruption of the Klotho gene in mice results in hypervitaminosis D and a syndrome resembling accelerated aging that includes osteopenia and vascular calcifications. Given that the bone microenvironment and its cellular components considerably influence hematopoiesis, in the present study, we addressed the in vivo role of klotho in blood cell formation and differentiation. Herein, we report that genetic ablation of Klotho in mice results in a significant increase in erythropoiesis and a decrease in the hematopoietic stem cell pool size in the bone marrow, leading to impaired hematopoietic stem cell homing in vivo. Our data also suggest that high vitamin D levels are only partially responsible for these hematopoietic changes in Klotho-/- mice. Importantly, we found similar hematopoietic abnormalities in Klotho-/- fetal liver cells, suggesting that the effects of klotho in hematopoietic stem cell development are independent of the bone microenvironment. Finally, injection of klotho protein results in hematopoietic changes opposite to the ones observed in Klotho -/- mice. These observations unveil a novel role for the antiaging hormone klotho in the regulation of prenatal and postnatal hematopoiesis and provide new insights for the development of therapeutic strategies targeting klotho to treat hematopoietic disorders associated with aging.

Original languageEnglish (US)
Pages (from-to)827-841
Number of pages15
JournalAmerican Journal of Pathology
Volume184
Issue number3
DOIs
StatePublished - Mar 2014

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Erythropoiesis
Hematopoietic Stem Cells
Hematopoiesis
Vascular Calcification
Cellular Microenvironment
Metabolic Bone Diseases
Bone Development
Chronic Renal Insufficiency
Cell Size
Vitamin D
Anemia
Cell Differentiation
Blood Cells
Bone Marrow
Hormones
Bone and Bones
Injections
Liver
Genes
Therapeutics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Klotho deficiency disrupts hematopoietic stem cell development and erythropoiesis. / Vadakke Madathil, Sangeetha; Coe, Lindsay M.; Casu, Carla; Sitara, Despina.

In: American Journal of Pathology, Vol. 184, No. 3, 03.2014, p. 827-841.

Research output: Contribution to journalArticle

Vadakke Madathil, Sangeetha ; Coe, Lindsay M. ; Casu, Carla ; Sitara, Despina. / Klotho deficiency disrupts hematopoietic stem cell development and erythropoiesis. In: American Journal of Pathology. 2014 ; Vol. 184, No. 3. pp. 827-841.
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