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Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies.

ABSTRACT: Infants with Down syndrome (DS) are at a high risk of developing transient abnormal myelopoiesis (TAM). A GATA1 mutation leading to the production of N-terminally truncated GATA1 (GATA1s) in early megakaryocyte/erythroid progenitors is linked to the onset of TAM and cooperated with the effect of trisomy 21 (Ts21). To gain insights into the underlying mechanisms of the progression to TAM in DS patients, we generated human pluripotent stem cells harbouring Ts21 and/or GATA1s by combining microcell-mediated chromosome transfer and genome editing technologies. In vitro haematopoietic differentiation assays showed that the GATA1s mutation blocked erythropoiesis irrespective of an extra chromosome 21, while Ts21 and the GATA1s mutation independently perturbed megakaryopoiesis and the combination of Ts21 and the GATA1s mutation synergistically contributed to an aberrant accumulation of skewed megakaryocytes. Thus, the DS model cells generated by these two technologies are useful in assessing how GATA1s mutation is involved in the onset of TAM in patients with DS.

SUBMITTER: Kazuki Y

PROVIDER: S-EPMC4145315 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies.

Kazuki Yasuhiro Y Yakura Yuwna Y Abe Satoshi S Osaki Mitsuhiko M Kajitani Naoyo N Kazuki Kanako K Takehara Shoko S Honma Kazuhisa K Suemori Hirofumi H Yamazaki Satoshi S Sakuma Tetsushi T Toki Tsutomu T Shimizu Ritsuko R Nakauchi Hiromitsu H Yamamoto Takashi T Oshimura Mitsuo M

Scientific reports 20140827

Infants with Down syndrome (DS) are at a high risk of developing transient abnormal myelopoiesis (TAM). A GATA1 mutation leading to the production of N-terminally truncated GATA1 (GATA1s) in early megakaryocyte/erythroid progenitors is linked to the onset of TAM and cooperated with the effect of trisomy 21 (Ts21). To gain insights into the underlying mechanisms of the progression to TAM in DS patients, we generated human pluripotent stem cells harbouring Ts21 and/or GATA1s by combining microcell ...[more]

PMID: 25159877

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Project description:Down syndrome (DS) subjects are more likely to develop the clinical features of Alzheimer's disease (AD) very early in the disease process due to the additional impact of neuroinflammation and because of activation of innate immunity. Many factors involved in the neuropathology of AD in DS, including epigenetic factors, innate immunity and impaired haematopoiesis, contribute significantly towards the pathophysiology and the enhanced ageing processes seen in DS and as a consequence of the triplication of genes RUNX1, S100β and OLIG2, together with the influence of proteins that collectively protect from cellular defects and inflammation, which include hepcidin, ferritin, IL-6 and TREM2. This study is aimed at determining whether genetic variants and inflammatory proteins are involved in haematopoiesis and cellular processes in DS compared with age-matched control participants, particularly with respect to neuroinflammation and accelerated ageing. Serum protein levels from DS, AD and control participants were measured by enzyme-linked immunosorbent assay (ELISA). Blood smears and post-mortem brain samples from AD and DS subjects were analysed by immunohistochemistry. RUNX1 mRNA expression was analysed by RT-PCR and in situ hybridisation in mouse tissues. Our results suggest that hepcidin, S100β and TREM2 play a critical role in survival and proliferation of glial cells through a common shared pathway. Blood smear analysis showed the presence of RUNX1 in megakaryocytes and platelets, implying participation in myeloid cell development. In contrast, hepcidin was expressed in erythrocytes and in platelets, suggesting a means of possible entry into the brain parenchyma via the choroid plexus (CP). The gene product of RUNX1 and hepcidin both play a critical role in haematopoiesis in DS. We propose that soluble TREM2, S100β and hepcidin can migrate from the periphery via the CP, modulate the blood-brain immune axis in DS and could form an important and hitherto neglected avenue for possible therapeutic interventions to reduce plaque formation.

Dataset Information

Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies.

Publications

Down syndrome-associated haematopoiesis abnormalities created by chromosome transfer and genome editing technologies.

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