Knockdown of Fanconi Anemia Genes in Human Embryonic Stem Cells Reveals Early Developmental Defects in the Hematopoietic Lineage

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2010 Jan 22

PMID 20089964

Citations 40

Authors

Asmin Tulpule

M William Lensch

Justine D Miller

Karyn Austin

Alan DAndrea

Thorsten M Schlaeger

Akiko Shimamura

George Q Daley

Affiliations

Soon will be listed here.

Abstract

Fanconi anemia (FA) is a genetically heterogeneous, autosomal recessive disorder characterized by pediatric bone marrow failure and congenital anomalies. The effect of FA gene deficiency on hematopoietic development in utero remains poorly described as mouse models of FA do not develop hematopoietic failure and such studies cannot be performed on patients. We have created a human-specific in vitro system to study early hematopoietic development in FA using a lentiviral RNA interference (RNAi) strategy in human embryonic stem cells (hESCs). We show that knockdown of FANCA and FANCD2 in hESCs leads to a reduction in hematopoietic fates and progenitor numbers that can be rescued by FA gene complementation. Our data indicate that hematopoiesis is impaired in FA from the earliest stages of development, suggesting that deficiencies in embryonic hematopoiesis may underlie the progression to bone marrow failure in FA. This work illustrates how hESCs can provide unique insights into human development and further our understanding of genetic disease.

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