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Updated: Oct 17, 2025
Isolation of Macrophage Subsets and Stromal Cells from Human and Mouse Myocardial Specimens
Published on: December 17, 2019
Cardiac Resident Macrophages Prevent Fibrosis and Stimulate Angiogenesis
Xavier S Revelo1,2, Preethy Parthiban1, Chen Chen3,4
1Department of Integrative Biology and Physiology (X.S.R., P.P., F.B., G.F., H.W., D.Y., J.H.v.B.), University of Minnesota, Minneapolis, MN, 55455.
Insights
Cardiac resident macrophages are key immune cells that promote blood vessel growth and reduce scarring early in heart pressure overload. Their depletion leads to worsened cardiac fibrosis and function.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cardiac Hypertrophy
Background:
- Cardiac pressure overload initially causes compensatory hypertrophy, but sustained stress leads to heart failure.
- Recruited macrophages influence the transition from compensated to decompensated hypertrophy.
- The role of cardiac resident immune cells in early hypertrophy remains unclear.
Purpose of the Study:
- To investigate the role of cardiac immune cells in the early stages of hypertrophy following pressure overload.
- To understand the specific contribution of cardiac resident macrophages to the initial hypertrophic response.
Main Methods:
- Flow cytometry and Cite-Seq single-cell RNA sequencing were used to analyze cardiac immune cells post-transverse aortic constriction (TAC).
- Macrophage colony-stimulating factor 1 receptor (CD115) blocking antibodies were employed to selectively deplete resident macrophages.
- CCR2 knockout mice were used to assess the role of monocyte-derived macrophages in fibrosis.
Main Results:
- TAC induced a significant increase in cardiac macrophages within one week.
- Selective depletion of resident macrophages resulted in enhanced cardiac fibrosis and impaired angiogenesis.
- Aggravated fibrosis was linked to the recruitment of monocyte-derived macrophages.
- Early depletion of resident macrophages led to depressed cardiac function and increased fibrosis at 6 weeks post-TAC.
Conclusions:
- Cardiac resident macrophages are a distinct immune cell population crucial for early cardiac adaptation to pressure overload.
- These cells play vital roles in promoting angiogenesis and mitigating fibrosis.
- Dysfunction or depletion of resident macrophages exacerbates adverse cardiac remodeling and dysfunction.
Rationale:
The initial hypertrophy response to cardiac pressure overload is considered compensatory, but with sustained stress, it eventually leads to heart failure. Recently, a role for recruited macrophages in determining the transition from compensated to decompensated hypertrophy has been established. However, whether cardiac resident immune cells influence the early phase of hypertrophy development has not been established.
Objective:
To assess the role of cardiac immune cells in the early hypertrophy response to cardiac pressure overload induced by transverse aortic constriction (TAC).
Methods And Results:
We performed cytometry by time-of-flight to determine the identity and abundance of immune cells in the heart at 1 and 4 weeks after TAC. We observed a substantial increase in cardiac macrophages 1 week after TAC. We then conducted Cite-Seq single-cell RNA sequencing of cardiac immune cells isolated from 4 sham and 6 TAC hearts. We identified 12 clusters of monocytes and macrophages, categorized as either resident or recruited macrophages, that showed remarkable changes in their abundance between sham and TAC conditions. To determine the role of cardiac resident macrophages early in the response to a hypertrophic stimulus, we used a blocking antibody against macrophage colony-stimulating factor 1 receptor (CD115). As blocking CD115 initially depletes all macrophages, we allowed the replenishment of recruited macrophages by monocytes before performing TAC. This preferential depletion of resident macrophages resulted in enhanced fibrosis and a blunted angiogenesis response to TAC. Macrophage depletion in CCR2 (C-C chemokine receptor type 2) knockout mice showed that aggravated fibrosis was primarily caused by the recruitment of monocyte-derived macrophages. Finally, 6 weeks after TAC these early events lead to depressed cardiac function and enhanced fibrosis, despite complete restoration of cardiac immune cells.
Conclusions:
Cardiac resident macrophages are a heterogeneous population of immune cells with key roles in stimulating angiogenesis and inhibiting fibrosis in response to cardiac pressure overload.
