TACKLING FUNCTIONAL MATURATION FOR TRANSPLANTABLE HEMATOPOIETIC STEM CELL GENERATION

Introduction

Hematopoietic stem cells (HSC) provide a lifelong supply of blood and immune cells. They are a life-saving therapy for leukemia and have recently found broadened applications to gene and cell therapy, against other cancers, genetic, autoimmune, and infectious diseases.

Limitations of Current Therapies

Nonetheless, practical limitations, such as donor-matching or insufficient cell number, render these therapies unfeasible or unsuccessful for many patients. Attempts to overcome these limitations have been unable to create a reliable source of HSC for patients.

Challenges in HSC Generation

While we can generate human HSC from pluripotent stem cells (PSC), they resemble early development stages, lacking the functional maturation hallmarks.

Objectives of FUN-HSC

FUN-HSC aims at identifying core and actionable maturation pathways for HSCs and at defining the contribution of coordinated gene expression by chromatin regulation. This will be achieved using a combination of functional and genetic screening technologies and high-throughput readouts in vitro and in vivo.

HSC Maturation Process

HSC maturation occurs in the liver during fetal development and confers functional multilineage hematopoiesis ability throughout adulthood. Using single-cell omics analysis of human embryonic and fetal tissues, we describe multiple gene programs changing during developmental HSC maturation.

Research Methodology

This study will lead to candidate cell-intrinsic and niche-dependent instructions, which will be dissected in the context of the fetal liver. The analysis will focus on:

1. Cell compartments and their interactions.
2. Combining novel organoid technologies with mouse xenografts to model the fetal liver environment.

Ultimate Goal

Ultimately, we aim to identify a strategy that mimics these pathways in vitro to bring the maturation stage of the PSC-derived HSC to a robustly engraftable and clinically valuable HSC source.

Conclusion

Harnessing new knowledge in human HSC biology, cutting-edge genetics, and tissue technologies, FUN-HSC will provide great advances in the mission of making and maintaining HSCs in vitro, enabling their full therapeutic potential.