Dataset Information

Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators.

ABSTRACT: Numerous human disorders of the blood system would directly or indirectly benefit from therapeutic approaches that reconstitute the hematopoietic system. Hematopoietic stem cells (HSCs), either from matched donors or ex vivo manipulated autologous tissues, are the most used cellular source of cell therapy for a wide range of disorders. Due to the scarcity of matched donors and the difficulty of ex vivo expansion of HSCs, there is a growing interest in harnessing the potential of pluripotent stem cells (PSCs) as a de novo source of HSCs. PSCs make an ideal source of cells for regenerative medicine in general and for treating blood disorders in particular because they could expand indefinitely in culture and differentiate to any cell type in the body. However, advancement in deriving functional HSCs from PSCs has been slow. This is partly due to an incomplete understanding of the molecular mechanisms underlying normal hematopoiesis. In this review, we discuss the latest efforts to generate human PSC (hPSC)-derived HSCs capable of long-term engraftment. We review the regulation of the key transcription factors (TFs) in hematopoiesis and hematopoietic differentiation, the Homeobox (HOX) and GATA genes, and the interplay between them and microRNAs. We also propose that precise control of these master regulators during the course of hematopoietic differentiation is key to achieving functional hPSC-derived HSCs.

SUBMITTER: Alsayegh K

PROVIDER: S-EPMC7062042 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators.

Alsayegh Khaled K Cortés-Medina Lorena V LV Ramos-Mandujano Gerardo G Badraiq Heba H Li Mo M

Current genomics 20190901 6

Numerous human disorders of the blood system would directly or indirectly benefit from therapeutic approaches that reconstitute the hematopoietic system. Hematopoietic stem cells (HSCs), either from matched donors or <i>ex vivo</i> manipulated autologous tissues, are the most used cellular source of cell therapy for a wide range of disorders. Due to the scarcity of matched donors and the difficulty of <i>ex vivo</i> expansion of HSCs, there is a growing interest in harnessing the potential of pl ...[more]

PMID: 32194342

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Project description:BackgroundHematopoiesis is a highly orchestrated developmental process that comprises various developmental stages of the hematopoietic stem cells (HSCs). During development, the decision to leave the self-renewing state and selection of a differentiation pathway is regulated by a number of transcription factors. Among them, genes GATA-1 and PU.1 form a core negative feedback module to regulate the genetic switching between the cell fate choices of HSCs. Although extensive experimental studies have revealed the mechanisms to regulate the expression of these two genes, it is still unclear how this simple module regulates the genetic switching.MethodsIn this work we proposed a mathematical model to study the mechanisms of the GATA-PU.1 gene network in the determination of HSC differentiation pathways. We incorporated the mechanisms of GATA switch into the module, and developed a mathematical model that comprises three genes GATA-1, GATA-2 and PU.1. In addition, a novel multiple-objective optimization method was designed to infer unknown parameters in the proposed model by realizing different experimental observations. A stochastic model was also designed to describe the critical function of noise, due to the small copy numbers of molecular species, in determining the differentiation pathways.ResultsThe proposed deterministic model has successfully realized three stable steady states representing the priming and different progenitor cells as well as genetic switching between the genetic states under various experimental conditions. Using different values of GATA-1 synthesis rate for the GATA-1 protein availability in the chromatin sites during the time period of GATA switch, stochastic simulations for the first time have realized different proportions of cells leading to different developmental pathways under various experimental conditions.ConclusionsMathematical models provide testable predictions regarding the mechanisms and conditions for realizing different differentiation pathways of hematopoietic stem cells. This work represents the first attempt at using a discrete stochastic model to realize the decision of HSC differentiation pathways showing a multimodal distribution.

Dataset Information

Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators.

Publications

Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators.

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