By Hendra Lukman 
The intricate machinery of the bone marrow, a constant powerhouse generating millions of fresh blood and immune cells every moment, relies on a delicate equilibrium. This vital process is orchestrated by hematopoietic stem cells (HSCs), supportive stromal cells, and a complex network of immune signals. However, as individuals age or face chronic inflammation and somatic mutations, this finely tuned balance can falter, disrupting communication pathways. This breakdown leads to a reduction in normal stem cell renewal and, critically, allows for the unchecked expansion of mutated HSCs. This phenomenon, known as clonal hematopoiesis of indeterminate potential (CHIP), is far from rare, affecting an estimated 10 to 20% of adults over 60 and nearly 30% of those over 80. While individuals with CHIP often remain asymptomatic, the condition significantly elevates their risk, increasing the likelihood of developing blood cancers by tenfold and doubling the risk of cardiovascular disease and premature death. A related, more severe disorder, myelodysplastic syndrome (MDS), also involves clonal HSCs but is characterized by inefficient blood cell production and progressive bone marrow failure. Affecting up to 20 in every 100,000 adults over 70, MDS carries a grim prognosis, with approximately 30% of cases advancing to acute myeloid leukemia (AML), an aggressive and frequently fatal malignancy. Despite the clear clinical implications of these conditions, the precise role of the bone marrow microenvironment – the ecosystem surrounding HSCs – in their development has remained an area of significant scientific inquiry.
Unveiling Hidden Cellular Shifts in the Bone Marrow Niche
A groundbreaking international research collaboration, co-led by Judith Zaugg from the European Molecular Biology Laboratory (EMBL) and the University of Basel, alongside Borhane Guezguez from the University Medical Center Mainz (UMC Mainz), has illuminated these hidden changes. Their extensive molecular and spatial analysis of human bone marrow samples, drawn from the BoHemE cohort study in partnership with Uwe Platzbecker at the National Center for Tumor Diseases (NCT) Dresden, provides unprecedented insight into the early stages of these blood disorders. Employing a sophisticated array of techniques, including single-cell RNA sequencing, biopsy imaging, proteomics, and co-culture models, the researchers meticulously constructed a detailed map of the bone marrow microenvironment in both healthy donors, including those with CHIP, and patients diagnosed with MDS.
The findings revealed a startling and unexpected cellular transformation that commences well before any clinical symptoms become apparent. The study identified a gradual displacement of the conventional mesenchymal stromal cells (MSCs), which are crucial for maintaining stem cell function, by a distinct population of inflammatory stromal cells.
“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,” stated Zaugg, a co-senior author, EMBL Group Leader, and Professor at Basel University. This observation is particularly significant as it suggests that the bone marrow microenvironment is not merely a passive bystander but an active participant in the early pathogenesis of these conditions.
The Inflammatory Cascade: From Stromal Cells to T-Cell Activation
The newly identified inflammatory MSCs (iMSCs) exhibit a distinct molecular profile compared to their healthy counterparts. They are characterized by the overproduction of interferon-induced cytokines and chemokines. These potent signaling molecules act as molecular attractants and activators for interferon-responsive T cells, thereby intensifying the inflammatory milieu within the bone marrow. This creates a self-perpetuating, feed-forward loop that sustains chronic inflammation. This persistent inflammation, in turn, is shown to disrupt normal blood formation processes and contribute to detrimental vascular changes within the bone marrow.
Deciphering the Drivers of Bone Marrow Inflammation
A critical aspect of the research involved disentangling the causal relationships. The team sought to determine whether the mutated hematopoietic cells themselves were the primary instigators of this inflammatory response. To achieve this, they employed SpliceUp, an innovative computational method developed by co-lead author Maksim Kholmatov, an EMBL alumnus, in collaboration with Pedro Moura and Eva Hellström-Lindberg from the Karolinska Institute. SpliceUp excels at identifying mutated cells within single-cell datasets by detecting aberrant RNA-splicing patterns, a hallmark of cellular genetic alterations.
Intriguingly, the analysis indicated that in MDS, the inflammatory network within the microenvironment becomes the dominant force, superseding and displacing much of the marrow’s normal regenerative architecture. Furthermore, the researchers discovered that mutated hematopoietic cells in MDS did not appear to directly trigger this pervasive inflammatory response.
“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,” explained Karin Prummel, a co-lead author and EMBL postdoctoral researcher. CXCL12 is a crucial chemokine that plays a vital role in guiding hematopoietic stem and progenitor cells to their appropriate niches within the bone marrow, facilitating their proper development and function. Its absence or diminished production could therefore significantly impair the bone marrow’s ability to regenerate healthy blood cells.
Maksim Kholmatov, also a co-lead author and EMBL alumnus, echoed this sentiment, stating, “It was quite surprising to see the lack of a direct inflammatory effect that we could attribute to the mutant cells. 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 that while mutated cells may be the initial "seeds" of disease, it is the altered microenvironment that cultivates and drives their malignant expansion.
Inflammation as a Crucial Early Driver of Blood Disorders
These pivotal findings strongly suggest that inflammation plays a central, indeed an early, role in the pathogenesis of blood disorders such as CHIP and MDS. The research emphatically positions the bone marrow microenvironment, often referred to as the bone marrow niche, as a critical therapeutic target. By shifting the focus from solely targeting mutated stem cells to understanding and intervening in the broader ecosystem that supports them, this work opens up new avenues for early treatment and prevention strategies.
The implications for therapeutic intervention are significant. The development of anti-inflammatory drugs or therapies designed to modulate interferon signaling pathways could potentially preserve bone marrow function in older adults who have CHIP, thereby mitigating their elevated risk of developing more severe conditions. Furthermore, a combined therapeutic approach, integrating targeted treatments that act directly on mutated cells with therapies that modulate the microenvironment, could prove instrumental in slowing or preventing the progression from CHIP to MDS or AML. The unique molecular signatures of iMSCs and interferon-responsive T cells also hold promise as early biomarkers, enabling the identification of individuals at elevated risk long before clinical manifestation.
“Our findings reveal that the bone marrow microenvironment actively shapes the earliest stages of malignant evolution,” emphasized Guezguez, a Principal Investigator in the Department of Hematology at UMC Mainz and co-senior author. “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.” This proactive approach to disease management could revolutionize the treatment paradigm for these serious blood disorders.
Broadening the Understanding of Age-Related Diseases and Inflammaging
Beyond the specific context of blood disorders, the research contributes substantially to a more comprehensive understanding of ‘inflammaging’ – the low-grade, chronic inflammation that is increasingly recognized as a fundamental contributor to a wide range of age-related conditions, including cancer, cardiovascular disease, and metabolic disorders. The bone marrow, once viewed primarily as a site of blood cell production, now emerges as a critical nexus, both susceptible to and actively involved in driving systemic inflammatory aging processes.
By elucidating the intricate interactions between immune cells and stromal cells that orchestrate these inflammatory changes within the bone marrow, the study offers a robust model for investigating similar inflammatory remodeling processes in other myeloid malignancies and advanced stages of leukemia.
“It will be crucial to study these processes over time; our current findings are based on cross-sectional data,” noted Zaugg. This longitudinal perspective is vital for understanding the dynamic nature of these changes. The findings also carry significant implications for existing therapeutic strategies, such as blood stem cell transplantation. If the bone marrow niche retains a "memory" of disease, even after the introduction of healthy stem cells, it could profoundly influence the long-term success and response rates of such treatments. The research team is actively investigating the extent to which the niche might retain this memory, a crucial step in optimizing future therapeutic interventions.
The publication of this study in Nature Communications is complemented by a parallel investigation into the MDS bone marrow microenvironment, also featured in the same issue. This complementary research, led by Marc Raaijmakers from Erasmus MC Cancer Institute in Rotterdam, further enhances the comprehensive understanding of inflammatory remodeling during the nascent stages of bone marrow disease, providing a more holistic view of these complex pathological processes.
The collaborative effort behind this research brought together institutions from across the globe, including UMC Mainz, University of Basel, University Hospital Dresden, Karolinska Institute Sweden, The Jackson Laboratory USA, and Sorbonne University, 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 project was provided by the DKTK-CHOICE program, an ERC grant (EpiNicheAML) awarded to Judith Zaugg, the MCSA-funded ITN ENHPATHY initiative, EMBO, the Swiss National Foundation, and the José Carreras Leukämie-Stiftung. This multidisciplinary and internationally supported endeavor underscores the global commitment to unraveling the complexities of blood disorders and age-related inflammatory processes.