# Characterizing the clonal dynamics and origins of the developing hematopoietic system

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2021 · $33,865

## Abstract

Project Summary/Abstract
Blood is a dynamic tissue that continuously regenerates, with replacement of approximately 1011 cells per day.
This process of hematopoiesis is driven by hematopoietic stem cells (HSCs) that have the capacity to make all
blood lineages upon transplantation. Notably, much of our knowledge of the hematopoietic system has come
from bulk transplantation or in vitro colony formation assays. The advent of novel lineage tracing methods and
single-cell technologies, however, has led to a dramatic shift in our view of HSCs. Indeed, as a population, they
have been shown to be remarkably heterogeneous, both transcriptionally and in terms of lineage output. Still
unresolved is how HSCs decide upon particular fates during development, and how these fate decisions are
altered during disease or aging.
As we continue to revise our view of HSCs, questions about the ontogeny of the hematopoietic system--from
where stem and progenitor cells arise, how they mature, and how they ultimately establish the nascent blood
system--are of significant biological and clinical interest. How many unique clones are active at a given time,
and do they act independently or as a consortium in generating downstream progeny? To trace blood
development in situ and at a clonal level, our lab has developed a novel genetic mouse model that utilizes
random transposon integration to barcode cells. Upon induction, each cell is marked by a stable, genetic tag
that is inherited by its progeny; at a later time, these tags can then be used to infer lineage relationships and
map developmental hierarchies. Due to the large diversity of possible barcodes, this tool will allow me to
lineage trace complex populations such as embryonic HSCs and, for the first time, clonally examine their
behavior in a native setting.
Here, I propose to utilize this tool to understand how blood stem and progenitor cells establish the
hematopoietic system and to generate a map of the hematopoietic hierarchy during development. First, I will
assess the number and contribution of HSCs that are specified during embryogenesis. Second, I will
characterize the origins and clonal dynamics of short-term HSCs and multipotent progenitors. Altogether, this
work will give unprecedented insight into the heterogeneity of HSC behavior and provide a platform to
investigate the mechanisms that govern particular fate decisions.

## Key facts

- **NIH application ID:** 10076565
- **Project number:** 5F30HL137235-04
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Sachin Hitesh Patel
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,865
- **Award type:** 5
- **Project period:** 2018-01-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10076565

## Citation

> US National Institutes of Health, RePORTER application 10076565, Characterizing the clonal dynamics and origins of the developing hematopoietic system (5F30HL137235-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10076565. Licensed CC0.

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