Researchers have tracked how circulating stem cells that support the lifelong production of blood and immune cells change across a person’s lifespan, which could simplify the diagnosis of blood cancers.
The findings, in Nature Medicine, provide reference ranges for these hematopoietic stem and progenitor cells (HSPCs) and could facilitate the clinical application of single-cell genomics in hematology. In particular, the study suggests that analyzing these cells could be useful to determining people at risk of diseases such as myelodysplastic syndrome. In this age-related group of disorders, blood stem cells fail to properly mature into functional blood cells.
“This study is the first to describe at the quantitative molecular level the variation in blood stem cells among healthy individuals,” said Amos Tanay, PhD, and Liran Shlush, PhD, who have a joint lab at the Weizmann Institute in Israel.
It is this variation that defines the boundaries of normal and allows the diagnosis of patterns that fall outside this, they explained to Inside Precision Medicine.
“This will advance blood malignancy diagnosis in general and specifically from the peripheral blood, replacing bone marrow analysis.” The study examined circulating HSPCs in 148 people from a range of ages using single-cell RNA sequencing of peripheral blood cells expressing the CD34 protein on their surface, together with computational methods.
The team tracked physiological and disease-specific changes in the participants through their lifespans and were able to characterize in detail the transcriptional programs of diverse, sometimes rare HSPC subpopulations, such as NKTDP and BEMP. They then defined the normal reference range for circulating HSPC subpopulation frequencies in the group of people studied.
This revealed that the composition of circulating HSPC subtypes varied greatly between different people, whereas the cell states themselves were remarkably general. These compositions remained stable during a year of follow up.
There was a remarkable, age-related increase in myeloid (MEBEMP) to lymphoid (CLP) progenitor ratios in men, when comparing those under 50 years of age with those over 60s. The age-related myeloid bias predominant in older men was not significant in women.
Within the MEBEMP differentiation trajectory, aging correlated with over-representation of more differentiated states, once again only in men.
This sex-specific correlation between age and circulating HSPC myeloid bias could be related to cell intrinsic properties, such as male-specific leukemia-associated mutations that predispose to myeloid differentiation, the researchers suggest.
Alternatively, it could be linked with age-related hormonal and bone-marrow microenvironmental changes.
The team then showed how myelodysplastic syndrome could be diagnosed from peripheral blood without bone marrow sampling, defining classes of patients with the condition and abnormal lymphocyte, basophil or granulocyte progenitor frequencies.
“Our study delves into the basic molecular physiology of [circulating] HSPCs at the population level, uncovering age-related phenotypes and proposing a platform for mechanistic and diagnostic insights into blood malignancies,” the researchers concluded.
“This resource, along with various other tools for profiling genetics and epigenomics in the blood, has the potential to redefine normal versus pathological states in hematology and provide both clinicians and researchers the means for mapping the transition from health to disease.”
