Image by James Thompson
Induced pluripotent stem cells (iPSCs) may help elucidate the pathogenesis of bone marrow failure (BMF) in Fanconi anemia (FA), researchers say.
They generated iPSCs from FA patients and found evidence suggesting that hematopoietic consequences originate at the earliest hematopoietic stage.
Specifically, hemoangiogenic progenitor cells (HAPCs) from FA-iPSCs produced significantly fewer hematopoietic and endothelial cells than controls.
“Although various consequences in hematopoietic stem cells have been attributed to FA-BMF, its cause is still unknown,” said study author Megumu K. Saito, MD, PhD, of Kyoto University in Japan.
“To address the issue, our team established iPSCs from 2 FA patients who have the FANCA gene mutation that is typical in FA. We were then able to obtain fetal-type immature blood cells [KDR+ CD34+ HAPCs] from these iPSCs.”
The researchers assessed differentiation in the FA-iPSC-derived HAPCs (FA-HAPCs) and found they produced significantly fewer CD34+ CD45+ hematopoietic precursors—and later, myeloid and erythroid lineage hematopoietic cells—than control cells. Likewise, FA-HAPCs produced fewer CD31+ endothelial cells than controls.
Cell cycle distribution in FA-HAPCs was comparable to that of controls, and FA-HAPCs were not apoptotic. This, according to the researchers, suggests a defect in FA-HAPCs’ ability to differentiate into hematopoietic and endothelial cells.
Further study of FA-HAPCs revealed significant downregulation of transcription factors that are critical for hematopoietic differentiation. This suggests the FA pathway might be involved in maintaining the transcriptional network critical for determining the differentiation propensity of HAPCs, the researchers said.
They also identified 227 genes that were significantly upregulated and 396 genes that were significantly downregulated in FA-HAPCs. The downregulated genes included those associated with mesodermal differentiation, vascular formation, and hematopoiesis.
“These data indicate that the hematopoietic consequences in FA patients originate from the earliest hematopoietic stage and highlight the potential usefulness of iPSC technology for explaining how FA-BMF occurs,” Dr Saito said.
“Since conducting a comprehensive analysis of patient-derived affected stem cells is not feasible without iPSC technology, the technology provides an unprecedented opportunity to gain further insight into this disease.”
Dr Saito and colleagues described this research in STEM CELLS Translational Medicine.
