Modulation of Hematopoietic Stem Cell Composition Holds Promise for Immune System Revitalization

Human immune system functions often gradually decline with aging, which not only weakens people’s resistance to foreign pathogens, but also makes vaccinations for the elderly generally less effective than those for younger people. A recent study by researchers at Stanford Medicine and the National Institute of Health’s Rocky Mountain Laboratories found that modulating the composition of hematopoietic stem cells in elderly mice helped revitalize their immune systems and improve their ability to fend off viral infections. The study, published in Nature on March 27, has the potential for future application to the human body, reversing the predicament of aging, which makes people susceptible to serious infections, as immunity declines.

Related article: Flow Cytometry-based Immunophenotyping for Quantifying Human Immunity and Promoting Precision Health 

Key Players in Human’s Immune Barriers

Hematopoietic stem cells (HSCs), as the name suggests, are stem cells responsible for hematopoiesis (formation of blood cellular components), possessing multipotency and self-renewal capabilities. The former allows HSCs to differentiate into all types of blood cells, including red blood cells, platelets, and various white blood cells (e.g., B cells, T cells, monocytes, macrophages, dendritic cells, etc.), while the latter allows HSCs to maintain their ability to differentiate over time, thereby continuing to produce the various types of blood cells needed by living organisms.

One of the main functions of HSCs is to build up the immune system of organisms by differentiating into lymphocytes and myelocytes (blood cells other than lymphocytes). This includes the innate immunity, which is composed primarily of myelocytes, responds in the same way to all invading substances (non-specific), retains no memory of previous infections, and is associated with inflammatory responses, as well as the adaptive immunity, which is composed primarily of lymphocytes (B-cells and T-cells), responds specifically to certain pathogens and develops an immune memory after the initial infection.

Imbalance in HSC Differentiation Could Compromise Immunity in the Elderly

It is noteworthy that the differentiation tendency of HSCs changes as organisms age. At younger ages, stem cell differentiation is more balanced and HSCs at this stage can be referred to as bal-HSCs. As organisms grow older, however, the differentiation tends to be myeloid-biased, and HSCs at this stage can be referred to as my-HSCs. When such imbalance occurs, lymphocyte production decreases while myelocyte production increases, which may weaken biological defenses against foreign pathogens. Moreover, myelocytes usually fight pathogens by triggering inflammatory responses, which may pose health hazards if they get too strong or become chronic. Besides, since vaccination mainly works on the body’s adaptive immunity, the above-mentioned phenomena may also compromise the protection of vaccines for older adults. 

Widely recognized as the “father of hematopoiesis”, Dr. Irving Weissman was the first scientist to isolate and purify HSCs in both mice and humans in the late 1980s. Since then, he and his colleagues have meticulously investigated the molecular details of these cells, trying to unravel the complex relationships among the cells that emerge as a result of those blood-forming stem cells.

As one of the corresponding authors of this research paper and currently a Professor of Pathology and Developmental Biology at Stanford University, Prof. Weissman cited the COVID-19 Pandemic as an example of the seriousness of the problem. As elderly people have fewer new B and T cell lymphocytes, they would be more vulnerable to SARS-CoV-2 infection than younger adults in general, leading to higher rates of severe illness and death in the elderly population. “This trend continued even after vaccinations became available. If we can revitalize the aging human immune system like we did in mice, it could be lifesaving when the next global pathogen arises,” said Prof. Weissman. 

Resetting the HSC Composition to Revive Aged Immune System

The researchers used mice aged 18 to 24 months as their study subjects. Considering that the average lifespan of laboratory mice lasts only about 2 to 3 years, these mice were considered to be old enough to live to this age. They treated the aged mice with antibodies targeting my-HSC for depletion of these myeloid-biased stem cells. The team found that the antibody-treated mice had more bal-HSC and higher numbers of new, naïve B and T cells than untreated animals. This implied that the mice’s immune system returned to a state similar to that of their younger counterparts. In addition, the treatment continued to exert its effects even two months after the administration of the antibody. When the treated mice received a vaccine against a virus that they had not previously encountered eight weeks later, their immune responses were stronger than those of the untreated mice. 

According to Jason Ross, MD, PhD, one of the lead authors of the study and a postdoctoral fellow at Stanford Medicine, not only did the team observe a change in differentiation patterns of HSCs in the antibody-treated group, resulting in the production of more lymphocytes involved in adaptive immunity, but they also saw a decrease in the levels of inflammatory proteins in those aged mice, which reduced the inflammation triggered by the invasion of a new pathogen. In addition, the effects of the treatment were longer than the team had expected. “Every feature of an aging immune system — functional markers on the cells, the prevalence of inflammatory proteins, the response to vaccination and the ability to resist a lethal infection — was impacted by this single course of treatment targeting just one cell type,” said Dr. Ross.

A Promising Key to Life-saving Therapies in Humans

Finally, the researchers also mentioned that since my-HSCs in mice and humans are very similar, it may be possible to test whether the above results can be reproduced in humans using similar techniques, or even lead to the development of new therapies that can reverse the aging of the human immune system, improve the response of the elderly to vaccinations, and minimize the damage caused by new viral infections in older individuals. 

“We believe that this study represents the first steps in applying this strategy in humans,” said Dr. Ross.

Author

Richard Chau