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Defects in Hematopoietic Stem Cell Function in a Mouse Model of Barth Syndrome

Barth syndrome (BTHS) is an X-linked monogenic recessive disorder characterized by cardiomyopathy, skeletal myopathy, and functional neutropenia. The neutropenia in BTHS can result in life-threatening bacterial infections; thus, patients are frequently treated with granulocyte colony-stimulating factor. While the
pathophysiologic mechanisms underlying the cardiac and skeletal muscle phenotypes have been extensively investigated, our understanding of the basis of the neutrophil defect remains poor. While several studies have examined mature neutrophils from BTHS patients and mouse models, few differences have been found. We have utilized a genetically accurate model of BTHS – the TAZ knockout (KO) mouse - to investigate alterations in hematopoietic development as a potential contributor to the BTHS neutrophil phenotype.

TAZ KO mice show a mild reduction in peripheral blood (PB) mature neutrophils as well as a significant expansion in bone marrow granulocyte-macrophage progenitors (GMPs). Compared to hematopoietic stem cells (HSCs) from WT littermate controls, TAZ KO HSCs produced fewer myeloid colonies (Fig. 1A), but no differences were observed in the number of colonies generated from committed myeloid progenitors from TAZ KO and WT mice. When purified HSCs were transplanted into lethally irradiated mice, TAZ KO HSCs showed a significant defect in long-term reconstitution capacity with significant defects in donor-derived B- and T cells. Recipients of TAZ KO HSCs also showed a tendency to generate fewer mature neutrophils and monocytes (Fig.1B). Taken together, these data indicate that TAZ KO HSCs exhibit a cell-intrinsic developmental defect resulting in reduced production of cells that comprise both the innate and adaptive immune systems. Such defects likely contribute to the recurrent infections observed in BTHS patients.

Recently, it has been reported that maintenance of HSC self-renewal depends on glycolysis. Given the importance of maintaining mitochondrial structural integrity for proper metabolic regulation, we tested whether the differentiation defect observed in TAZ KO HSCs is due to differential responses to glucose levels. Using a
custom methylcellulose culture system established to modify glucose concentrations, we observed that TAZ KO and WT HSCs gave rise to comparable numbers of colonies when cultured under low glucose levels as opposed to standard (high glucose) culture conditions (Fig.1C). These findings suggest that TAZ deficiency
results in HSC defects in neutrophil/monocyte development in response to their metabolic environment, thereby providing a rationale for potential interventional strategies that limit serum glucose levels.

Mohamed Ali1, Nainita Bhowmick1, Iryna Berezniuk1, Sohini Chakraborty1, Mindong Ren3,4, Colin Phoon2 and Christopher Y. Park1

  1. Department of Pathology, New York University Grossman School of Medicine, New York, NY
  2. Department of Pediatric Cardiology/Pediatrics, New York University Grossman School of Medicine, New York, NY
  3. Department of Anesthesiology, New York University Grossman School of Medicine, New York, NY
  4. Department ofCell Biology, New York University Grossman School of Medicine, New York, NY

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