Bone Marrow-Derived NGFR+ Dendritic Cells Regulate Arterial Remodeling

Background Introduction

Atherosclerosis is the primary pathological basis of cardiovascular disease, and its incidence continues to rise globally. Although extensive research has revealed the pathogenesis of atherosclerosis and led to the development of various therapeutic drugs, some risk factors remain incompletely understood. Recent studies have found that bone marrow plays a crucial role in the pathogenesis of atherosclerosis, but its specific mechanism remains unclear. In particular, the interaction between bone marrow and peripheral blood (the bone marrow-peripheral axis) is considered critical in the initiation and progression of atherosclerosis.

Nerve Growth Factor Receptor (NGFR), also known as p75NTR or CD271, is a receptor for nerve growth factors widely expressed in bone marrow stromal cells, peripheral blood, and ischemic coronary arteries. NGFR not only participates in the development and repair of the nervous system but also plays a dual role in cell survival and apoptosis. Previous studies have shown that NGFR is expressed in atherosclerotic plaques, but its specific function in arterial remodeling remains incompletely elucidated.

Based on this background, researchers proposed a hypothesis: bone marrow-derived NGFR-positive (NGFR+) cells may regulate arterial remodeling and inhibit the development of atherosclerosis. To test this hypothesis, the researchers designed a series of experiments to explore the mechanisms of NGFR+ cells after arterial injury and assess their potential clinical applications.

Source of the Paper

This paper was completed by researchers from the Department of Cardiovascular Medicine at Kanazawa University, including Shinichiro Takashima and Soichiro Usui, with additional collaborators from the Public Central Hospital of Matto Ishikawa and Kanazawa University. The paper was published on January 2, 2025, in the journal American Journal of Physiology-Cell Physiology, titled “Bone Marrow-Derived NGFR-Positive Dendritic Cells Regulate Arterial Remodeling.”

Research Process and Results

1. Animal Models and Bone Marrow Transplantation Experiments

The researchers first constructed a mouse carotid artery ligation model to simulate the remodeling process after arterial injury. By comparing wild-type (WT) mice and NGFR knockout (KO) mice, they found that neointima formation significantly increased after carotid artery ligation in NGFR-KO mice. This indicates that NGFR plays an important role in inhibiting arterial remodeling.

To further verify the role of bone marrow-derived NGFR+ cells, the researchers conducted bone marrow transplantation (BMT) experiments. They transplanted bone marrow from NGFR-WT or NGFR-KO mice expressing green fluorescent protein (GFP) into recipient mice. The results showed that mice transplanted with NGFR-KO bone marrow exhibited significantly increased neointima formation after carotid artery ligation, with more active proliferation of smooth muscle cells (SMCs) in the neointima. This result confirms the critical role of bone marrow-derived NGFR+ cells in suppressing arterial remodeling.

2. Apoptosis of NGFR+ Cells and Accumulation of Anti-Inflammatory Macrophages

The researchers further explored the specific mechanisms of NGFR+ cells after arterial injury. Through immunohistochemical analysis, they discovered that NGFR+ cells accumulated in the neointima and underwent apoptosis. Additionally, the presence of NGFR+ cells promoted the accumulation of anti-inflammatory macrophages, which express Mannose Receptor C-Type 1 (MRC1) and secrete the anti-inflammatory cytokine IL-10, thereby inhibiting the proliferation of smooth muscle cells.

In vitro co-culture experiments further validated this mechanism. Researchers co-cultured NGFR+ mononuclear cells (MNCs) from human peripheral blood with aortic smooth muscle cells and found that NGFR+ cells were more prone to apoptosis when stimulated by the nerve growth factor precursor (Pro-NGF). Moreover, NGFR+ cells exhibited chemotaxis towards nerve growth factor (NGF), indicating that NGFR+ cells are attracted to the site of injury where they undergo apoptosis.

3. Clinical Study: Relationship Between NGFR+ Cells and Acute Coronary Syndrome

To evaluate the potential clinical application value of NGFR+ cells, the researchers conducted a prospective cohort study involving 30 patients with acute coronary syndrome (ACS). The study found that the number of NGFR+ mononuclear cells in the peripheral blood of ACS patients significantly increased on the third day after the onset of ACS. Furthermore, patients with insufficient numbers of NGFR+ cells exhibited more significant intimal progression in non-target lesions after nine months. Multivariate regression analysis showed that the number of NGFR+ cells is an independent risk factor for intimal progression over nine months.

Conclusions and Significance

The conclusions of this study indicate that bone marrow-derived NGFR+ dendritic cells (DCs) suppress arterial remodeling through apoptotic mechanisms, promote the accumulation of anti-inflammatory macrophages, and inhibit the proliferation of smooth muscle cells. This discovery provides a new perspective on the pathogenesis of atherosclerosis and reveals the potential therapeutic value of NGFR+ cells in combating atherosclerosis.

Research Highlights

1. Novelty: This study is the first to reveal the role of bone marrow-derived NGFR+ dendritic cells in arterial remodeling, proposing a new concept where NGFR+ cells inhibit atherosclerosis through apoptosis and the accumulation of anti-inflammatory macrophages.
2. Clinical Application Value: The study found that an insufficient number of NGFR+ cells is an independent risk factor for intimal progression in ACS patients, providing a new biomarker for clinical prognosis assessment.
3. Innovative Experimental Design: Researchers systematically validated the functional mechanisms of NGFR+ cells in arterial remodeling through bone marrow transplantation models and in vitro co-culture experiments.

Future Prospects

Despite significant progress, there are still some issues that need further exploration. For example, the specific interaction mechanisms between NGFR+ cells and macrophages remain unclear and can be further analyzed using technologies like single-cell sequencing. Additionally, this study mainly relied on the carotid artery ligation model, and future research can validate the role of NGFR+ cells in high-fat diet or ApoE gene knockout mouse models.

The findings of this study provide new insights into the treatment of atherosclerosis, and it is hoped that by modulating the number or function of NGFR+ cells, more effective anti-atherosclerosis treatment strategies can be developed in the future.