Maturing hematopoietic progenitors derived from iPSCs to optimize human models of MDS
Date
2023
DOI
Authors
Ultmann Fierstein, Sara Rose
Version
Embargo Date
2026-03-13
OA Version
Citation
Abstract
Myelodysplastic syndromes (MDS) encompass a heterogeneous group of age-related hematopoietic disorders characterized by ineffective and incomplete hematopoiesis leading to an increased risk of acute myeloid leukemia (AML). The development of accurate and easily used in vitro models is crucial for understanding the pathogenesis of MDS and identifying potential therapeutic targets. Induced pluripotent stem cells (iPSCs) can be used to study MDS due to their ability to differentiate into any cell type depending on the environment. The main limitation is that the blood progenitors produced by iPSCs are of a fetal state, which hinders modeling of MDS, a disease of older adulthood. This study aimed to optimize the maturation state of blood progenitors derived from iPSCs by induction of the micro-RNA let-7, which, we hypothesize will increase the maturation and adult phenotypic state of hematopoietic progenitors.
iPSC lines were generated from healthy controls and samples containing the SRSF2 mutation, a common mutation in MDS, containing a doxycycline-inducible, stabilized let-7 transgene. A stepwise differentiation efficiently drove the iPSCs toward hematopoietic progenitors and, subsequently, other mature lineages. The hematopoietic progenitors were characterized by assessing the expression of specific cell surface markers and functional properties using flow cytometry, colony-forming assays, and multi-lineage differentiation abilities. These findings demonstrate the potential of using iPSC engineering to create a novel model for MDS and other age-biased disorders by inducing let-7 expression in iPSCs and, when differentiating them, exposing them to doxycycline to promote an adult cell phenotype. This approach offers a valuable potential tool for elucidating the molecular mechanisms underlying these disorders and exploring potential therapeutic interventions.