Inflammatory Pathways and the Bone Marrow Microenvironment in Inherited Bone Marrow Failure Syndromes

Pediatrics Hematology Immunology Basic Medical Sciences Cell Biology Biochemistry Oncology Genetics Life Sciences Medicine
inherited bone marrow failure syndromes inflammation pro-inflammatory cytokines bone marrow microenvironment mesenchymal stromal cells hematopoietic stem cells cytokine network

Inflammatory Pathways and Bone Marrow Microenvironment in Inherited Bone Marrow Failure Syndromes: New Insights into Chronic Inflammation

Research Background and Academic Significance

Inherited bone marrow failure syndromes (IBMFS) are a group of genetic disorders characterized by reduced hematopoietic cell production due to blood stem cell dysfunction. They include the commonly seen Fanconi anemia (FA), Diamond-Blackfan anemia (DBA), and Shwachman-Diamond syndrome (SDS). These diseases present with multi-system clinical manifestations, often involving anemia, bleeding, immunodeficiency, and a high risk of malignancy at a young age.

In recent years, advances in genomics and fundamental medicine have clarified the genetic basis and inherent stem cell dysfunction of these diseases. However, our understanding is still limited regarding the roles and mechanistic impact of the bone marrow microenvironment (BME) and inflammation in disease onset and progression. The bone marrow is a complex organ composed of various hematopoietic and non-hematopoietic cells (such as mesenchymal stem cells, endothelial cells, perivascular stromal cells, etc.). The bone marrow microenvironment not only supports the self-renewal and differentiation of hematopoietic stem cells (HSCs), but also regulates hematopoietic homeostasis via multiple soluble factors.

In the bone marrow of patients with IBMFS, chronic inflammation manifests as sustained elevation of several pro-inflammatory cytokines (such as tumor necrosis factor-α [TNF-α], interleukin-1β [IL-1β], interleukin-6 [IL-6], transforming growth factor-β [TGF-β], type I interferon [IFN-I], interferon-γ [IFN-γ], etc.). Inflammation not only directly damages the hematopoietic system but also disrupts the function of stromal support cells such as mesenchymal stem cells in the bone marrow microenvironment, eventually leading to HSC exhaustion and bone structural abnormalities. It is urgent to systematically review the roles and mechanisms of inflammation and the microenvironment in IBMFS, in order to promote the development of anti-chronic inflammation interventions and improve patient prognosis. Therefore, this review focuses on the interplay between inflammatory pathways and the bone marrow microenvironment in IBMFS, synthesizing recent advances in the field to provide a theoretical foundation for future intervention strategies.

Source of the Paper and Author Information

The paper, titled “Inflammatory pathways and the bone marrow microenvironment in inherited bone marrow failure syndromes,” was published in the April 29, 2025 issue of STEM CELLS (2025, 43, sxaf021). The author team includes Nicholas Neoman, Hye Na Kim, Jacob Viduya, Anju Goyal, Y Lucy Liu, and Kathleen M Sakamoto, all from the Division of Hematology/Oncology/Stem Cell Transplantation and Regenerative Medicine at Stanford University School of Medicine, USA. Kathleen M. Sakamoto is the corresponding author. This paper, an invited concise review, provides a high-level overview of advances in the field over the previous five years.

Content Structure and Main Viewpoints

This paper is not a single, original experimental study, but a systematic review that focuses on summarizing the mechanisms of inflammation and their impact on the bone marrow microenvironment in IBMFS. The text revolves around the following themes:

1. Pathogenic Basis and Inflammatory Features of IBMFS

The paper first systematically presents the genetic background, hematopoietic defects, and high cancer risk of the IBMFS family (including FA, DBA, and SDS). Although these three diseases each have distinct genetic defects—resulting in DNA repair defects, ribosomal protein deficiencies, or abnormal ribosome assembly—they all share the features of chronic cellular stress, accumulation of reactive oxygen species (ROS), and excessive expression of pro-inflammatory cytokines. The authors argue that abnormally elevated pro-inflammatory cytokines not only damage hematopoietic stem cells, but also affect endothelial cells and mesenchymal stem cells, undermining the support function of the hematopoietic microenvironment. The article cites several recent studies—including single-cell RNA sequencing, quantification of inflammatory factors in patient blood and bone marrow, and animal models—to support the central role of inflammation in IBMFS pathophysiology.

Supporting evidence: - Single-cell studies found that CD3+ T cells and CD56+ NK cells in DBA and FA bone marrow produce large amounts of TNF-α and IFN-γ (Reference 12). - In vitro cultures show that MSCs from FA patients have decreased self-renewal and differentiation capacity, closely related to damage from pro-inflammatory factors (References 49, 50). - Animal models confirm that upregulation of TNF-α and TGF-β significantly inhibits FA and SDS stem cell function, which can be partially reversed by specific inhibitors (References 40, 13).

2. Detailed Analysis of the Inflammatory Mechanisms in Each IBMFS Subtype

1. Fanconi anemia (FA)

FA centers on DNA interstrand crosslink repair defects, involving 23 related gene mutations and ALDH2 enzyme dysfunction that predispose to DNA damage accumulation. Accumulated DNA damage triggers activation of the p53/p21 signaling pathway, leading to cell cycle arrest and HSPC exhaustion. Due to mitochondrial dysfunction, ROS increases continually, accompanied by downregulation of antioxidant gene expression. FA cells are highly sensitive to pro-inflammatory factors such as TNF-α and TGF-β, readily undergoing premature senescence and apoptosis. Moreover, MSCs from FA patients tend to differentiate into adipocytes, show impaired osteogenesis, and fail to effectively support HSPCs. Studies also point to defective development of endothelial cells in FA patients, aggravating bone marrow failure.

Supporting evidence: - FA triggers increased cellular stress mediated by p53/p21 due to DNA repair defects (Reference 25). - FA cells have diminished ROS scavenging ability and simultaneous defects in MSC differentiation (References 26, 49). - High levels of TNF-α, TGF-β1, and TGF-β3 are detectable in the serum of FA patients, inhibiting the growth of HSPCs (References 32, 40).

2. Diamond-Blackfan anemia (DBA)

DBA is mainly caused by heterozygous mutations in ribosomal protein genes (such as RPS19, RPL11, etc.) and severely impairs erythropoiesis. Protein synthesis defects lead to globin and heme synthesis imbalance, resulting in excessive free heme accumulation and elevated ROS in early erythroid cells, causing cell death (including ferroptosis). ROS-induced DNA damage further activates pro-inflammatory factor expression. The latest single-cell transcriptomic results further reveal that MSCs of bone marrow origin in DBA patients show differentiation abnormalities, which is an important mechanism underlying bone development disorders and increased risk of osteosarcoma.

Supporting evidence: - Both animal models and patient-derived cells demonstrate elevated ROS and increased levels of pro-inflammatory factors (TNF-α, IL-1β, IL-6, IFN-γ) (References 66, 69). - The decreased antioxidant capacity in DBA patients exacerbates genetic damage, while inhibition of pro-inflammatory factors pharmacologically can alleviate some phenotypes (References 66, 69, 70). - DBA patients often present with skeletal abnormalities and increased osteosarcoma risk, indicating MSCs impairment (References 72, 73).

3. Shwachman-Diamond syndrome (SDS)

SDS is caused by biallelic mutations in the SBDS gene, disrupting ribosome assembly. SBDS deficiency increases cellular sensitivity to DNA damage and ROS, leading to reduced stem cell activity, and abnormal autophagy and stress responses. During hematopoiesis, SBDS-defective CD34+ cells show significantly upregulated TNF-α expression and NF-κB-mediated pro-inflammatory responses. MSCs from SDS patients have compromised support capacity, accompanied by osteoporosis and impaired bone development. Of particular note, compensatory somatic TP53 mutations may help relieve some cell cycle blockage, but are prone to lead to myelodysplastic transformation and other malignant evolution.

Supporting evidence: - SBDS deficiency induces increased ROS, while MDS and bone marrow variants commonly exhibit somatic mutations like TP53 and isochromosome 7q (References 74, 83, 84). - Animal and iPSC models show that SBDS insufficiency affects early hematopoiesis, endothelial cell generation, and MSC differentiation, with sustained activation of inflammatory signals (s100a8/a9, TGF-β3) (References 80, 88, 13).

3. IBMFS Commonalities and Microenvironmental Mechanism Integration

The authors summarize that, despite being caused by different genetic abnormalities, these three IBMFS share the following features: - Early onset: Most cases present in infancy or childhood. - Chronic inflammation and bone marrow microenvironment destruction are common, with various pro-inflammatory cytokines elevated, increased ROS burden, HSC exhaustion, and functional disorder. - Damage to mesenchymal stem cells, endothelial cells, hematopoietic support functions, and osteogenesis leads to anemia-like phenotypes. - High susceptibility to malignancy is a common trait among all patients, aligning with Dameshek’s paradox (patients with hypoproliferative diseases are ironically more likely to develop highly proliferative tumors). - Transcriptomic analyses reveal that, in spite of genetic heterogeneity, several diseases exhibit convergent expression profiles in pathways related to protein synthesis, redox metabolism, and cell stress, providing a theoretical basis for overarching interventions.

4. Conclusions and Outlook: Prospects for Anti-inflammation and Microenvironment-targeted Interventions

The article highlights that the “core commonality” in IBMFS pathogenesis lies in chronic oxidative stress (ROS), cell cycle disorder, and persistent pro-inflammatory environment. Inflammation not only damages hematopoietic stem cells, but further weakens microenvironmental support, exacerbating disease. While the genetic backgrounds of these diseases differ, inflammatory pathways are emerging as promising targets for precision therapy. The article advocates for deeper integration of single-cell omics, cell biology, animal models, and clinical interventions to clarify key nodes in both inflammatory networks and MSC microenvironmental disruption. Anti-inflammatory and antioxidant strategies, and drugs targeting pathways such as TNF-α and TGF-β, may break through the bottleneck of hematopoietic reconstruction and reduction of malignant transformation.

Academic Value and Significance of the Paper

  1. Theoretical Innovation: This paper systematically integrates recent foundational and clinical research, clearly proposing the central roles of inflammatory pathways and the bone marrow microenvironment in IBMFS pathogenesis and identifying them as new therapeutic targets.
  2. Methodological Value: The paper extensively references multi-disciplinary techniques such as single-cell genomics, gene editing, animal models, transcriptomics, and proteomics, advancing mechanistic understanding and drug development.
  3. Clinical Prospects: Provides a theoretical basis and practical direction for future IBMFS treatment paradigms—for example, intervention in pro-inflammatory signaling, enhancing MSC microenvironmental quality, and blocking ROS production may restore hematopoietic homeostasis and improve prognosis in children.
  4. Disciplinary Integration: Fosters interdisciplinary integration among genetics, stem cell biology, immune inflammation, and tissue regeneration, serving as a model for research into other complex hematopoietic diseases.
  5. Looking Forward: The paper calls for the field’s focus on therapeutic targeting of inflammation and the microenvironment in IBMFS patients, with the expectation that scientific understanding will drive clinical translation, ultimately benefiting affected children.

Other Valuable Information

  • All figures in the paper were created with BioRender, enhancing visualization and comprehension.
  • The study reports funding and support from NIH, the American Society of Hematology, DOD Bone Marrow Failure Program, DBA Foundation, Stanford Maternal Child Health Research Institute, and CIRM, highlighting the authority and forefront nature of the research project.
  • The authors’ acknowledgments and disclosures section demonstrates the team’s rigor and neutrality in writing the paper.

In summary, this high-quality review published in STEM CELLS systematically reviews the molecular mechanisms of inflammation and microenvironmental interaction in inherited bone marrow failure syndromes, highlights the scientific and practical value of chronic inflammation as a novel therapeutic target, and is highly valuable for promoting progress in both fundamental and clinical research.