How is blood (re-)made? Regeneration of human hematopoietic stem cells after transplantation

Introduction

How hematopoietic stem and progenitor cells (HSPCs) regenerate blood is a major unsolved question, frustrating their effective use for therapy. Every year, over 40,000 patients receive an HSPC transplantation (HSCT) as a last-resort therapy for various diseases, including leukemia.

Challenges in HSCT

However, approximately 40% of HSCT recipients die due to poor outgrowth of the donor HSPCs, inflammatory complications, or relapse. There is an unmet need for strategies to predict and prevent these adverse outcomes.

Current Understanding

In mice, single-cell methods have revolutionized our understanding of how hematopoiesis is organized, allowing us to control the outcome of murine HSCT in detail. In contrast, our understanding of human hematopoietic regeneration, and our ability to control this process, is lagging behind.

Mission Statement

As a clinician in pediatric HSCT and stem cell biologist, my mission is to change this. RESTART aims to comprehensively characterize the cellular and molecular mechanisms guiding hematopoietic regeneration in humans.

Methodology

I have pioneered single-cell methods to study human HSPC biology. Here, we will apply state-of-the-art multiomics to dissect the identities and functional states of thousands of HSPCs and their surrounding niche cells in human bone marrow (BM).

Research Context

Embedded in Europe’s largest pediatric cancer center, we will apply these methods to a unique, longitudinal collection of BM samples of pediatric HSCT recipients and their donors, collected before and up to a year after HSCT.

Objectives

Our objectives are:

1. Dissect the cellular and molecular composition of the HSPC population during successful hematopoietic regeneration in human HSCT recipients.
2. Determine how HSCT-induced alterations in BM niche cells affect HSPC fate.
3. Leverage this information to identify and validate single-cell states or trajectories predictive of adverse HSCT outcomes (graft failure, relapse).

Expected Impact

This study will contribute to improved survival of human HSCT recipients and to increased fundamental knowledge on human tissue regeneration.