# Accumulation of Lymphoid Progenitors with Defective B Cell Differentiation and of Putative Natural Killer Progenitors in Aging Human Bone Marrow

## TL;DR

This study identifies age-related changes in human bone marrow, including the accumulation of cells with impaired B cell development and memory-like natural killer progenitors.

## Contribution

The study reveals a novel hallmark of aging in the human lymphoid compartment: the accumulation of defective B progenitors and memory-like NK progenitors.

## Key findings

- Aging human bone marrow shows a reduction in early B progenitors.
- An aging-related lymphoid cluster accumulates, with cells showing defective B differentiation.
- Memory-like natural killer progenitors make up 9.4% of this aging-related cluster.

## Abstract

In animal models, elimination of the senescent cells in the hematopoietic stem cells (HSCs) compartment leads to the rejuvenation of hematopoiesis. Whether this treatment principle can be applied to the human system remains controversial. The identification of senescent cells in human bone marrow poses another major challenge. To address these questions, we have studied hematopoietic stem and progenitor cells (HSPCs, CD34+) from the bone marrow of 15 healthy human subjects (age range: 19–74 years). Single-cell RNA sequencing, functional transcriptome analysis, and development trajectory studies were performed. In a previous report, we demonstrated the accumulation of a senescent population in the aging HSC compartment. The present study focuses on the differences with age downstream in the lymphoid trajectory. While a reduction in B progenitors in the early lymphoid compartment can be confirmed, the accumulation of a lymphoid cluster downstream upon aging is novel and remarkable. This cluster comprises cells with a significant deficiency in B differentiation markers, as well as 9.4% cells with transcriptome signatures of memory-like natural killer (NK) progenitors. Applying our analysis algorithm to other human bone marrow datasets from the literature, we are able to validate the presence of this unique cluster in aged lymphoid progenitors. The accumulation of a population comprising cells defective in B differentiation potential, as well as cells with transcriptome features of memory-like NK progenitors represents a novel hallmark for senescence in the late development trajectory of human lymphoid compartment.