Inducible pluripotent stem cell models to study bone marrow failure and MDS predisposition syndromes.

IF 2.5 4区 医学 Q2 HEMATOLOGY Experimental hematology Pub Date : 2024-11-02 DOI:10.1016/j.exphem.2024.104669
Sushree S Sahoo, Majd Khiami, Marcin W Wlodarski
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Abstract

Induced pluripotent stem cells (iPSCs) have emerged as powerful tools for in vitro modeling of bone marrow failure (BMF) syndromes and hereditary conditions predisposing to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). This review synthesizes recent advances in iPSC-based disease modeling for various inherited BMF/MDS disorders, including Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia syndrome, Shwachman-Diamond syndrome, and severe congenital neutropenia as well as GATA2, RUNX1, ETV6, ANKRD26, SAMD9, SAMD9L, and ADH5/ALDH2 syndromes. Although the majority of these iPSC lines are derived from patient cells, some are generated by introducing patient-specific mutations into healthy iPSC backgrounds, offering complementary approaches to disease modeling. The review highlights the ability of iPSCs to recapitulate key disease phenotypes, such as impaired hematopoietic differentiation, telomere dysfunction, and defects in DNA repair or ribosome biogenesis. We discuss how these models have enhanced our understanding of disease pathomechanisms, hematopoietic defects, and potential therapeutic approaches. Challenges in generating and maintaining disease-specific iPSCs are examined, particularly for disorders involving DNA repair. We emphasize the necessity of creating isogenic controls to elucidate genotype-phenotype relationships. Furthermore, we address limitations of current iPSC models, including genetic variability among iPSC clones derived from the same patient, and difficulties in achieving robust engraftment of iPSC-derived hematopoietic progenitor cells in mouse transplantation models. The review also explores future directions, including the potential of iPSC models for drug discovery and personalized medicine approaches. This review underscores the significance of iPSC technology in advancing our understanding of inherited hematopoietic disorders and its potential to inform novel therapeutic strategies.

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研究骨髓衰竭和 MDS 易感综合征的可诱导多能干细胞模型。
诱导多能干细胞(iPSC)已成为骨髓衰竭(BMF)综合征以及易患骨髓增生异常综合征(MDS)和急性髓性白血病(AML)的遗传性疾病体外建模的有力工具。本综述综述了基于 iPSC 的疾病建模在治疗各种遗传性 BMF/MDS 疾病方面的最新进展,这些疾病包括范可尼贫血症、先天性角化不良、Diamond Blackfan 贫血综合征、Shwachman-Diamond 综合征、严重先天性中性粒细胞减少症以及 GATA2、RUNX1、ETV6、ANKRD26、SAMD9、SAMD9L 和 ADH5/ALDH2 综合征。虽然这些 iPSC 株系大多来自患者细胞,但也有一些是通过在健康 iPSC 背景中引入患者特异性突变产生的,为疾病建模提供了补充方法。综述强调了 iPSC 重现关键疾病表型的能力,如造血分化受损、端粒功能障碍、DNA 修复或核糖体生物发生缺陷。我们将讨论这些模型如何增进我们对疾病病理机制、造血缺陷和潜在治疗方法的了解。我们探讨了生成和维持疾病特异性 iPSCs 所面临的挑战,尤其是涉及 DNA 修复的疾病。我们强调了建立同源对照的必要性,以阐明基因型与表型之间的关系。此外,我们还讨论了当前 iPSC 模型的局限性,包括来自同一患者的 iPSC 克隆之间的遗传变异,以及在小鼠移植模型中实现 iPSC 衍生造血祖细胞稳健移植的困难。综述还探讨了未来的发展方向,包括 iPSC 模型在药物发现和个性化医疗方法方面的潜力。这篇综述强调了 iPSC 技术在增进我们对遗传性造血疾病的了解方面的重要意义,及其为新型治疗策略提供信息的潜力。
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来源期刊
Experimental hematology
Experimental hematology 医学-血液学
CiteScore
5.30
自引率
0.00%
发文量
84
审稿时长
58 days
期刊介绍: Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.
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