By Hendra Lukman 
Every moment, the bone marrow tirelessly generates millions of fresh blood and immune cells, a constant process of renewal that hinges on a delicate equilibrium. This vital ecosystem relies on the intricate interplay between hematopoietic stem cells (HSCs), supportive stromal cells, and a complex network of immune signals. However, as individuals age, this finely tuned balance can become increasingly vulnerable. Factors such as chronic inflammation or the accumulation of somatic mutations can disrupt the crucial communication pathways between these cellular components. This disruption leads to a decline in normal HSC renewal and, more insidiously, allows mutated HSCs to proliferate and expand undetected. This phenomenon is known as clonal hematopoiesis of indeterminate potential (CHIP), a condition that affects a significant portion of the aging population. Current estimates suggest that CHIP is present in approximately 10% to 20% of adults over 60, with the prevalence rising sharply to nearly 30% in those over 80.
While individuals diagnosed with CHIP typically remain asymptomatic, the condition carries substantial health risks. It elevates the risk of developing blood cancers by a tenfold margin and is associated with a doubled likelihood of experiencing cardiovascular disease and premature mortality. A related, more severe disorder is myelodysplastic syndrome (MDS). MDS involves the proliferation of clonal HSCs that are incapable of producing sufficient numbers of healthy blood cells, leading to a gradual failure of bone marrow function. This condition impacts an estimated 20 out of every 100,000 adults over the age of 70. Alarmingly, approximately 30% of MDS cases progress to acute myeloid leukemia (AML), an aggressive and often fatal form of blood cancer. Despite the gravity of these blood disorders, the precise role of the bone marrow microenvironment – the intricate niche that houses and supports blood stem cells – in their development has remained a significant area of uncertainty for researchers.
Mapping Hidden Changes in the Bone Marrow Microenvironment
To unravel the mechanisms by which mutated HSC clones gain dominance within the bone marrow, an international consortium of researchers, co-led by Judith Zaugg from the European Molecular Biology Laboratory (EMBL) and the University of Basel, and Borhane Guezguez from the University Medical Center (UMC) Mainz, embarked on an extensive molecular and spatial analysis of human bone marrow samples. This groundbreaking research drew upon data from the BoHemE cohort study, a collaborative effort involving Uwe Platzbecker at the National Center for Tumor Diseases (NCT) Dresden.
Employing a sophisticated array of techniques, including single-cell RNA sequencing, advanced biopsy imaging, proteomics, and meticulously designed co-culture models, the research team meticulously constructed a detailed molecular and spatial map of the bone marrow microenvironment. This comprehensive map encompassed samples from healthy donors, including those diagnosed with CHIP, as well as patients with MDS. Their analysis yielded a surprising revelation: a profound cellular shift begins to occur long before any outward clinical signs of disease manifest. The researchers observed a gradual replacement of the typical mesenchymal stromal cells (MSCs) – cells crucial for supporting HSC function – by a distinct population of inflammatory stromal cells.
Judith Zaugg, a co-senior author on the study, EMBL Group Leader, and Professor at the University of Basel, expressed her astonishment at the findings. "I was surprised to observe such pronounced remodeling of the bone marrow microenvironment already in individuals with CHIP, although the underlying cause-and-effect relationships remain unclear," she stated. This early remodeling suggests that the bone marrow niche itself undergoes significant alterations, potentially setting the stage for future disease development.
Unlike healthy stromal cells, these newly identified inflammatory MSCs (iMSCs) exhibit a distinct functional profile. They are characterized by the production of substantial quantities of interferon-induced cytokines and chemokines. These signaling molecules act as potent attractants, drawing in and activating interferon-responsive T cells. In turn, these activated T cells amplify the inflammatory activity within the bone marrow, creating a self-perpetuating, or "feed-forward," loop. This chronic inflammatory cycle disrupts the normal processes of blood formation and can contribute to detrimental vascular changes within the marrow.
Identifying the Drivers of Bone Marrow Inflammation
A critical question for the researchers was whether the mutated hematopoietic cells themselves directly initiated this inflammatory cascade in MDS. To address this, they employed SpliceUp, a sophisticated computational method developed by co-lead author and EMBL alumnus Maksim Kholmatov, in collaboration with Pedro Moura and Eva Hellström-Lindberg from the Karolinska Institute. SpliceUp is designed to identify mutated cells within single-cell datasets by detecting aberrant RNA-splicing patterns, a hallmark of cellular mutations.
Through this advanced analysis, the researchers discovered that in MDS, the inflammatory network within the microenvironment becomes the dominant force, displacing and eroding the bone marrow’s normal regenerative architecture. Crucially, they did not find direct evidence that the mutated hematopoietic cells in MDS were the primary instigators of this pervasive inflammatory response.
Karin Prummel, a co-lead author and EMBL postdoc, highlighted another significant observation. "Another striking observation was that MDS stem cells couldn’t trigger stromal cells to produce CXCL12, an important signal that triggers blood cells to settle in the bone marrow. This failure may help explain why the bone marrow stops working properly," she explained. CXCL12 plays a vital role in anchoring hematopoietic cells to their supportive niche, and its absence could contribute to the inefficient blood cell production seen in MDS.
Maksim Kholmatov further elaborated on the unexpected nature of their findings. "It was quite surprising to see the lack of a direct inflammatory effect that we could attribute to the mutant cells," he commented. "However, when viewed in the context of changes in the T cell and stromal compartments, it underlines the importance of the bone marrow microenvironment in shaping disease progression." This suggests a paradigm shift, where the environment, rather than solely the mutated cells, plays a pivotal role in driving the disease.
Inflammation as an Early Driver of Blood Disease
The cumulative findings from this research strongly indicate that inflammation plays a central and early role in the pathogenesis of these blood disorders. This underscores the bone marrow microenvironment, often referred to as the bone marrow niche, as a critical target for therapeutic intervention. By shifting the focus from the mutated stem cells themselves to the complex ecosystem that supports their proliferation and survival, this research opens up new avenues for early detection, treatment, and prevention strategies.
The implications for therapeutic development are profound. The introduction of anti-inflammatory drugs or therapies designed to modulate interferon signaling pathways could potentially help preserve bone marrow function in older adults who have CHIP. Furthermore, combining targeted treatments aimed at specific molecular pathways with therapies that actively modify the bone marrow microenvironment might offer a strategy to slow or even prevent the progression from CHIP to more severe conditions like MDS or AML. The unique molecular signatures of iMSCs and interferon-responsive T cells identified in this study could also serve as valuable early biomarkers, enabling the identification of individuals at an elevated risk of developing these blood disorders.
Borhane Guezguez, Principal Investigator in the Department of Hematology at UMC Mainz and co-senior author, emphasized the forward-looking nature of the research. "Our findings reveal that the bone marrow microenvironment actively shapes the earliest stages of malignant evolution," he stated. "As advances in molecular profiling allow us to detect pre-leukemic states years before clinical onset, understanding how stromal and immune cells interact provides a foundation for preventive therapies that intercept disease progression before leukemia develops."
Inflammaging and the Wider Impact on Age-Related Disease
The significance of these findings extends beyond the realm of blood disorders, offering valuable insights into the broader phenomenon of ‘inflammaging.’ Inflammaging refers to the low-grade, chronic inflammation that is increasingly recognized as a contributing factor to a wide range of age-related conditions, including various cancers, cardiovascular diseases, and metabolic disorders. The bone marrow, once primarily viewed as a passive site of blood production, now appears to be both a recipient of and a contributor to systemic inflammatory aging processes. By elucidating the intricate interactions between immune cells and stromal cells that drive these age-related changes, this study provides a compelling model for investigating similar inflammatory remodeling processes in other myeloid malignancies and advanced stages of leukemia.
Judith Zaugg highlighted the importance of longitudinal studies to further solidify these findings. "It will be crucial to study these processes over time; our current findings are based on cross-sectional data," she noted. This temporal aspect has significant implications, particularly for therapies such as blood stem cell transplantation, which aim to replace malignant cells but leave the bone marrow niche intact. "We are now investigating to what extent the niche retains a ‘memory’ of disease, which could shape how it responds to new, healthy stem cells," she added. Understanding this potential "memory" could be key to optimizing the success of such regenerative therapies.
The research published in Nature Communications is complemented by a parallel study also appearing in the same journal. This complementary work, led by Marc Raaijmakers from Erasmus MC Cancer Institute in Rotterdam, focuses on the MDS bone marrow microenvironment. Together, these two studies offer a more comprehensive and integrated understanding of the inflammatory remodeling processes that occur during the nascent stages of bone marrow diseases.
The collaborative effort involved researchers from a multitude of prestigious institutions, including UMC Mainz, the University of Basel, University Hospital Dresden, the Karolinska Institute in Sweden, The Jackson Laboratory in the USA, and Sorbonne University in France, along with partner institutions of the German Cancer Consortium (DKTK), such as the German Cancer Research Center (DKFZ) and NCT Dresden. Funding for this extensive research was provided by the DKTK-CHOICE program, an ERC grant awarded to Judith Zaugg (EpiNicheAML), the MCSA-funded ITN ENHPATHY, EMBO, the Swiss National Science Foundation, and the José Carreras Leukemia Foundation. This multifaceted support highlights the international recognition of the importance and potential impact of this groundbreaking work.