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Delayed Intramyocardial Delivery of Stem Cells after Ischemia Reperfusion Injury in a Murine Model
Published on: September 3, 2020
Modulation of bone marrow haematopoietic stem cell activity as a therapeutic strategy after myocardial infarction: a
Jasmin Rettkowski1,2,3,4, Mari Carmen Romero-Mulero1,3, Indranil Singh5,6
1Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Insights
Myocardial infarction (MI) harms bone marrow hematopoietic stem cells (HSCs). Targeting HSCs with vitamin A derivatives can reduce inflammation and improve heart function after MI.
Area of Science:
- Cardiovascular Research
- Hematology
- Stem Cell Biology
Background:
- Myocardial infarction (MI) poses a significant global health challenge.
- While myeloid cells aid post-MI tissue repair, excessive myelopoiesis can worsen cardiac scarring and function.
- The role of bone marrow hematopoietic stem cells (HSCs) in emergency hematopoiesis post-MI remains unclear.
Purpose of the Study:
- To investigate the impact of MI on human bone marrow HSCs.
- To determine if HSCs contribute to pro-inflammatory myeloid cell infiltration in cardiac tissue post-MI.
- To explore therapeutic strategies targeting HSCs to improve cardiac function after MI.
Main Methods:
- Collected human sternal bone marrow samples from cardiac surgery patients.
- Analyzed transcriptional and functional changes in HSCs post-MI.
- Utilized lineage tracing experiments to track HSC contributions.
- Investigated the therapeutic potential of 4-oxo-retinoic acid to enforce HSC quiescence.
Main Results:
- MI induces detrimental transcriptional and functional alterations in human bone marrow HSCs.
- Lineage tracing indicates HSCs contribute to pro-inflammatory myeloid cells in cardiac tissue post-MI.
- Enforcing HSC quiescence with 4-oxo-retinoic acid reduced inflammatory myelopoiesis.
Conclusions:
- Human bone marrow HSCs are negatively impacted by MI and contribute to cardiac inflammation.
- Therapeutic enforcement of HSC quiescence with 4-oxo-retinoic acid shows promise for modulating cardiac remodeling and preserving function post-MI.
Abstract:
Myocardial infarction (MI) is a major global health concern. Although myeloid cells are crucial for tissue repair in emergency haematopoiesis after MI, excessive myelopoiesis can exacerbate scarring and impair cardiac function. Bone marrow (BM) haematopoietic stem cells (HSCs) have the unique capability to replenish the haematopoietic system, but their role in emergency haematopoiesis after MI has not yet been established. Here we collected human sternal BM samples from over 150 cardiac surgery patients, selecting 49 with preserved cardiac function. We show that MI causes detrimental transcriptional and functional changes in human BM HSCs. Lineage tracing experiments suggest that HSCs are contributors of pro-inflammatory myeloid cells infiltrating cardiac tissue after MI. Therapeutically, enforcing HSC quiescence with the vitamin A metabolite 4-oxo-retinoic acid dampens inflammatory myelopoiesis, thereby modulating tissue remodelling and preserving long-term cardiac function after MI.
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