Modulation of Bone Marrow Haematopoietic Stem Cell Activity as a Therapeutic Strategy After Myocardial Infarction: A Preclinical Study

Hematology Immunology Cell Biology Cardiovascular System Life Sciences Medicine
myocardial infarction bone marrow haematopoietic stem cells inflammation vitamin A metabolites cardiac function

Academic Background

Myocardial Infarction (MI) is one of the major global health concerns. Although myeloid cells in the bone marrow (BM) are crucial for tissue repair after MI, excessive myelopoiesis can exacerbate scarring and impair cardiac function. Hematopoietic stem cells (HSCs) in the bone marrow possess unique regenerative capabilities, enabling the replenishment of the hematopoietic system. However, the role of HSCs in emergency hematopoiesis (EH) following MI remains incompletely understood. Previous studies have shown that HSCs in mouse models proliferate and functionally decline after MI, but whether HSCs directly contribute to the generation of immune cells infiltrating the heart remains unclear. Additionally, therapeutic strategies targeting systemic inflammation post-MI have yielded inconsistent results in clinical studies, highlighting the urgent need for new and specific treatment approaches.

Source of the Study

This research was conducted by a collaborative team from multiple international research institutions, including the University of Freiburg in Germany and ETH Zurich in Switzerland, among others. The research team was led by Jasmin Rettkowski, Mari Carmen Romero-Mulero, and other scholars. The paper was published in April 2025 in the journal Nature Cell Biology, titled “Modulation of Bone Marrow Haematopoietic Stem Cell Activity as a Therapeutic Strategy after Myocardial Infarction: A Preclinical Study.”

Research Process and Results

1. Patient Sample Collection and Preliminary Analysis

The research team collected sternal bone marrow samples from over 150 patients undergoing cardiac surgery and selected 49 patients with preserved cardiac function, dividing them into control and MI groups. Through single-cell RNA sequencing (scRNA-seq) analysis, the team found that MI led to significant transcriptional and functional changes in BM HSCs. Specifically, the number of HSCs decreased, while the numbers of multipotent progenitors (MPPs) and multilymphoid primed progenitors (MLPs) increased. Gene Set Enrichment Analysis (GSEA) revealed that stemness-related genes in HSCs were downregulated, while cell cycle activation-related genes were upregulated after MI.

2. In Vitro Functional Experiments

To assess the functionality of HSCs post-MI, the team conducted in vitro colony-forming unit (CFU) assays. The results showed that HSCs from MI patients exhibited enhanced colony formation in the first plating but significantly reduced colony formation in the second plating, indicating impaired self-renewal capacity. Further in vivo transplantation experiments confirmed that HSCs from MI patients exhibited a significant decline in long-term reconstitution ability.

3. Monocyte Analysis

The research team also performed scRNA-seq analysis on BM monocytes, revealing that the trajectory of monocyte generation shifted from common myeloid progenitors (CMPs) to classical, intermediate, and non-classical monocytes post-MI. CMP levels significantly increased during the acute phase, while the chronic phase showed an increase in cycling monocytes. GSEA analysis indicated that monocytes exhibited a pro-inflammatory signature during the acute phase, which persisted into the chronic phase.

4. HSC Lineage Tracing in Mouse Models

To verify whether HSCs directly contribute to the generation of immune cells infiltrating the heart post-MI, the research team used the Fgd5CreERT2 mouse model for lineage tracing. The results showed that HSCs differentiated into myeloid progenitors (MyPs) and myeloid cells significantly increased after MI. Through immunofluorescence staining and flow cytometry, the team detected a large number of HSC-derived myeloid cells, including neutrophils, macrophages, and inflammatory monocytes, in the infarcted heart tissue.

5. Regulation by Vitamin A Metabolites

The research team further explored the regulatory role of vitamin A metabolites on HSCs. In vitro experiments demonstrated that all-trans retinoic acid (AT-RA) and its downstream metabolite 4-oxo-retinoic acid (4-Oxo-RA) enhanced HSC stemness features and reduced their differentiation. However, in vivo experiments revealed that while AT-RA inhibited HSC activation, it induced a pro-inflammatory response in cardiac myeloid cells, thereby limiting its therapeutic effects on post-MI cardiac repair. In contrast, 4-Oxo-RA, by specifically binding to the RARβ receptor, maintained HSC quiescence and significantly improved cardiac function post-MI.

6. Long-Term Effects of 4-Oxo-RA

In mouse models, 4-Oxo-RA treatment significantly reduced the infiltration of HSC-derived myeloid cells into the heart and improved cardiac function post-MI. Through scRNA-seq, the research team found that cardiac myeloid cells after 4-Oxo-RA treatment exhibited lower inflammatory signatures and an increased proportion of reparative macrophages. Additionally, 4-Oxo-RA treatment reduced collagen deposition post-MI and significantly improved left ventricular ejection fraction (LVEF).

Conclusions and Significance

This study is the first to reveal the mechanisms of HSC activation and functional decline post-MI and to demonstrate that HSCs directly contribute to the generation of inflammatory myeloid cells infiltrating the heart. By specifically modulating HSC quiescence using 4-Oxo-RA, the research team successfully suppressed excessive myelopoiesis and improved cardiac function post-MI. This discovery provides a new therapeutic strategy for MI, targeting HSC activity to inhibit inflammation and enhance cardiac repair.

Research Highlights

  1. Role of HSCs Post-MI: First to demonstrate the direct contribution of HSCs in emergency hematopoiesis post-MI and to elucidate the mechanisms of their functional decline.
  2. Therapeutic Potential of Vitamin A Metabolites: 4-Oxo-RA, by specifically binding to the RARβ receptor, maintains HSC quiescence and significantly improves cardiac function post-MI.
  3. Application of Lineage Tracing Technology: Using the Fgd5CreERT2 mouse model, the research team successfully traced the infiltration of HSC-derived myeloid cells into the heart.
  4. In-Depth Analysis via scRNA-seq: Through scRNA-seq, the research team revealed the transcriptional changes in HSCs and monocytes post-MI, providing a molecular basis for understanding their functions.

Additional Valuable Information

The study also explored the limitations of AT-RA in MI treatment, noting that its non-specific binding may induce a pro-inflammatory response in cardiac myeloid cells, thereby limiting its therapeutic efficacy. This finding suggests that AT-RA should be used with caution in clinical applications, and more specific agents like 4-Oxo-RA should be prioritized.

This research not only provides a new strategy for MI treatment but also offers important scientific insights into the role of HSCs in emergency hematopoiesis.