What does your blood remember? The memory of hematopoietic stem cells.

Introduction

Human organism produces over a million new blood cells each second. The hematopoietic system dynamically reacts to environmental stress and forms adaptive immunity to memorize and effectively fight the encountered pathogens. However, based on our recent studies and preliminary results, we propose that the adaptive capabilities and memory of the hematopoietic system reach far beyond the classical adaptive antigen-specific immunity.

Hypothesis

We hypothesize that hematopoietic stress induces clonal expansion of lineage-biased hematopoietic stem cells (HSCs) with epigenetic memory that faster and more effectively respond to secondary stimulation with a given stress factor.

Lineage-Biased HSCs

We propose that lineage-biased HSCs accumulating during aging provide a broad adaptive memory of the hematopoietic system, which is not restricted to immune cells but includes all blood cell lineages.

Aim of the Proposal

The aim of our proposal is to understand how the HSC-stored memory is created, maintained, and recalled, and to clarify the underlying mechanisms.

Research Approach

1. Granulopoiesis, Erythropoiesis, and Thrombopoiesis
   First, we will selectively stimulate granulopoiesis, erythropoiesis, and thrombopoiesis to define the specificity and physiological role of hematopoietic memory provided by HSCs, both in vitro and in vivo.

2. Single-Cell Level Fate Mapping and Sequencing
   Second, we will use single-cell level fate mapping and sequencing to investigate clonal and epigenetic mechanisms driving the HSCs-based memory in mice.

3. Aging Pool of Human HSCs
   Third, we will test if the aging pool of human HSCs consists of lineage-biased HSCs that store memory of the previously encountered stimuli. The humanized mice models will determine the clonal expansion of human HSCs upon primary and secondary stimulation with stress factors.

Expected Outcomes

Altogether, the expected outcome of the project is to understand how and why the hematopoietic system adjusts to environmental challenges upon aging. The proposed novel concept of the hematopoietic system adaptivity may help to design strategies to train patients' hematopoiesis and improve the transplantations of HSCs.