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| Status |
Public on Apr 02, 2024 |
| Title |
Primitive macrophages induce sarcomeric maturation and functional enhancement of contractile human cardiac microtissues via efferocytic pathways |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The first macrophages that seed the developing heart originate from the yolk sac during fetal life. While murine studies reveal important homeostatic and reparative functions in adults, we know little about their roles in the earliest stages of human heart development due to a lack of accessible tissue. Generation of bioengineered human cardiac microtissues from pluripotent stem cells models these first steps in cardiac tissue development, however macrophages have not been included in these studies. To bridge these gaps, we differentiated human embryonic stem cells (hESCs) into primitive LYVE1+ macrophages (hESC-macrophages; akin to yolk sac macrophages) that stably engrafted within cardiac microtissues composed of hESC-cardiomyocytes and fibroblasts to study reciprocal interactions. Engraftment induced a tissue resident macrophage gene program resembling human fetal cardiac macrophages, enriched in efferocytic pathways. Functionally, hESC-macrophages induced production and maturation of cardiomyocyte sarcomeric proteins, and enhanced contractile force, relaxation kinetics, and electrical properties. Mechanistically, the primary effect of hESC-macrophages was during early microtissue formation, where they engaged in phosphatidylserine dependent ingestion of apoptotic cardiomyocyte cargo, which reinforced core resident macrophage identity, reduced microtissue stress and drove hESC-cardiomyocytes to become more similar to human ventricular cardiomyocytes found in early development, both transcriptionally and metabolically. Inhibiting efferocytosis of hESC-cardiomyocytes by hESC-macrophages led to increased cell stress, impaired sarcomeric protein maturation and reduced cardiac microtissue function (contraction and relaxation). Taken together, macrophage-engineered human cardiac microtissues represent a considerably improved model for human heart development, and reveal a major beneficial, yet previously unappreciated role for human primitive macrophages in enhancing cardiac tissue function.
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| Overall design |
We generated immuno-engineered human cardiac microtissues to investigate hESC-macrophage education and their subsequent role in cardiomyocyte function. We performed gene expression profiling (bulk RNA-seq) of sorted hESC-macrophages (day 14; N=3 per group) and hESC-cardiomyocytes (day 3; N=4 per group).
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| Web link |
https://www.nature.com/articles/s44161-024-00471-7
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| Contributor(s) |
Hamidzada H, Epelman S |
| Citation(s) |
39086373 |
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| Submission date |
Mar 14, 2024 |
| Last update date |
Aug 26, 2024 |
| Contact name |
Slava Epelman |
| E-mail(s) |
slava.epelman@uhn.ca
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| Organization name |
University Health Network
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| Street address |
101 College St.
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| City |
Toronto |
| State/province |
Ontario |
| ZIP/Postal code |
M5G 1L7 |
| Country |
Canada |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (26)
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| GSM8147619 |
Biowire, macrophages from CMFBMF, replicate 1 |
| GSM8147620 |
Biowire, macrophages from CMFBMF, replicate 2 |
| GSM8147621 |
Biowire, macrophages from CMFBMF, replicate 3 |
| GSM8147622 |
Biowire, macrophages from FBMF, replicate 1 |
| GSM8147623 |
Biowire, macrophages from FBMF, replicate 2 |
| GSM8147624 |
Biowire, macrophages from FBMF, replicate 3 |
| GSM8147625 |
Biowire, macrophages from MF group, replicate 1 |
| GSM8147626 |
Biowire, macrophages from MF group, replicate 2 |
| GSM8147627 |
Biowire, macrophages from MF group, replicate 3 |
| GSM8147628 |
Digested control cells, macrophages from CMFBMF, replicate 1 |
| GSM8147629 |
Digested control cells, macrophages from CMFBMF, replicate 2 |
| GSM8147630 |
Digested control cells, macrophages from CMFBMF, replicate 3 |
| GSM8147631 |
Digested control cells, macrophages from FBMF, replicate 1 |
| GSM8147632 |
Digested control cells, macrophages from FBMF, replicate 2 |
| GSM8147633 |
Digested control cells, macrophages from FBMF, replicate 3 |
| GSM8147634 |
Digested control cells, macrophages alone, replicate 1 |
| GSM8147635 |
Digested control cells, macrophages alone, replicate 2 |
| GSM8147636 |
Digested control cells, macrophages alone, replicate 3 |
| GSM8147637 |
Biowire, cardiomyocytes from CM+FB, replicate 1 |
| GSM8147638 |
Biowire, cardiomyocytes from CM+FB, replicate 2 |
| GSM8147639 |
Biowire, cardiomyocytes from CM+FB, replicate 3 |
| GSM8147640 |
Biowire, cardiomyocytes from CM+FB, replicate 4 |
| GSM8147641 |
Biowire, cardiomyocytes from CM+FB+MF, replicate 1 |
| GSM8147642 |
Biowire, cardiomyocytes from CM+FB+MF, replicate 2 |
| GSM8147643 |
Biowire, cardiomyocytes from CM+FB+MF, replicate 3 |
| GSM8147644 |
Biowire, cardiomyocytes from CM+FB+MF, replicate 4 |
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| Relations |
| BioProject |
PRJNA1088134 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE261628_NormalizedCounts_BiowireMF.xlsx |
2.3 Mb |
(ftp)(http) |
XLSX |
| GSE261628_NormalizedCounts_CM.xlsx |
2.3 Mb |
(ftp)(http) |
XLSX |
| GSE261628_NormalizedCounts_ControlCells.xlsx |
2.1 Mb |
(ftp)(http) |
XLSX |
| GSE261628_RawCounts_BiowireMF.xlsx |
925.6 Kb |
(ftp)(http) |
XLSX |
| GSE261628_RawCounts_CM.xlsx |
1.2 Mb |
(ftp)(http) |
XLSX |
| GSE261628_RawCounts_ControlCells.xlsx |
1.1 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
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