Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time Window of Cardiomyocyte Proliferation and Myocardial Regeneration.
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ABSTRACT:
SUBMITTER: Nakada Y
PROVIDER: S-EPMC9202233 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
Single Nucleus Transcriptomics: Apical Resection in Newborn Pigs Extends the Time Window of Cardiomyocyte Proliferation and Myocardial Regeneration.
Nakada Yuji Y Zhou Yang Y Gong Wuming W Zhang Eric Y EY Skie Erik E Nguyen Thanh T Wei Yuhua Y Zhao Meng M Chen Wangping W Sun Jiacheng J Raza S Naqi SN Chen Jake Y JY Walcott Gregory P GP Garry Daniel J DJ Zhang Jianyi Jay JJ
Circulation 20220606 23
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Project description:Background: In this study, we have extended the myocardial regenerative window to postnatal day 28 (P28) by a double injury pig model (ARP1MIP28) of apical resection at P1 (ARP1) and LAD ligation at P28 (MIP28). However, the molecular mechanism of regenerative window extension is not known. Results: Gene-expression profiles revealed that regenerating ARP1MIP28 hearts contained different subpopulations of cardiomyocytes early after 2nd injury. The six cardiomyocyte clusters were identified (CM1-CM6) by Louvain clustering. The CM6, CM3, and CM2 clusters have mainly consisted of fetal (92.4%), CTL-P1 (95.7%), and CTL-P56 (96.2%) cardiomyocytes. In contrast, the CM1 cluster has consisted of heterogeneous cardiomyocyte groups from all other animal groups, including less than 1% of fetal and CTL-P1 cardiomyocytes. The CM5 and CM4 clusters have mainly consisted of ARP1MIP28-P35 cardiomyocytes, 97.8%, and 68.6%, respectively. Sparse modeling analysis revealed that AR and MI injury, both alone and in combination, appeared to promote the proliferative capacity of cardiomyocytes and perturb cardiomyocyte maturation. Publication: This dataseries is associated to manuscript titled 'Single nucleus transcriptomics: Apical resection in newborn pigs extends the time-window of cardiomyocyte proliferation and myocardial regeneration', published in Circulation, 2021.
2021-10-06 | GSE185289 | GEO
Project description:Single nucleus transcriptomics: Apical resection in newborn pigs extends the time-window of cardiomyocyte proliferation and myocardial regeneration
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Project description:The neonatal heart completely regenerates after apical resection (AR), providing a desirable research model to study the mechanism of cardiac regeneration and cardiomyocyte proliferation. However, AR-induced neonatal heart regenerative phenomenon is controversial due to the variation of operative details in different laboratories. Here, we provide an optimized AR operation procedure with stable regeneration and high survival rate by achieving heart exposure, normalizing myocardium cut-offs, and reducing operation duration. We also established a whole-heart-slice approach to estimate the myocardial regeneration after the AR operation, which ensures no false-negative/positive results. The combination of the optimized AR operation and the whole-heart-slice analysis provides a stable system to study neonatal heart regeneration and cardiomyocyte proliferation in situ.
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Project description:The finding that neonatal mice are able to regenerate myocardium after apical resection has recently been questioned. We determined if heart regeneration is influenced by the size of cardiac resection and whether surgical retraction of the ventricular apex results in an increase in cardiomyocyte cell cycle activity. We performed moderate or large apical ventricular resections on neonatal mice and quantified scar infiltration into the left ventricular wall at 21 days post-surgery. Moderately resected hearts had 15±2% of the wall infiltrated by a collagen scar; significantly greater scar infiltration (23±4%) was observed in hearts with large resections. Resected hearts had higher levels of cardiomyocyte cell cycle activity relative to sham hearts. Surgically retracting the ventricle often resulted in fibrosis and induced cardiomyocyte cell cycle activity that were comparable to that of resected hearts. We conclude that apical resection in neonatal mice induces cardiomyocyte cell cycle activity and neomyogenesis, although scarring can occur. Surgical technique and definition of approach to assessing the extent of regeneration are both critical when using the neonatal mouse apical resection model.
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Project description:Background: When pigs underwent apical resection (AR) on postnatal day (P) 1 (ARP1) followed by myocardial infarction (MI) on P28, the hearts had little evidence of scarring; meanwhile, hearts underwent MI on P28 without ARP1 showed large infarcts on P56; and the improvement of ARP1 hearts was driven primarily by cardiomyocyte proliferation. AR and MI were performed ~5 mm (AR) and ~20 mm (MI) above the heart apex; thus, we hypothesize that ARP1 preserved the cardiomyocytes cell-cycle throughout the left ventricle, rather than only near the resection site. Methods: Sections of cardiac tissue were collected from the left ventricle of uninjured pigs and from both the border zone (BZ) of AR and uninjured regions (remote zone, [RZ]) in ARP1 hearts. Cardiomyocyte proliferation was evaluated via immunofluorescence analysis of phosphorylated histone 3 [PH3] and symmetric Aurora B (sAuB). Single nucleus RNA sequencing (snRNAseq) data collected from the hearts of fetal pigs, uninjured pigs, and the BZ and RZ of ARP1 pigs was evaluated via our cell-cycle-specific Autoencoder to identify proliferating cardiomyocytes. Results: Cardiomyocyte PH3 and sAuB expression, and percentage of proliferating cardiomyocytes in snRNA data was significantly more common in both BZ and RZ of ARP1 than uninjured hearts but did not differ significantly between the ARP1-BZ and ARP1-RZ at any time point. Heat shock protein HSPA5 and HSP90B1 were overexpressed at both ARP1-BZ and ARP1-RZ. In AC16 cell, overexpression (and knockdown) of HSPA5-HSP90B1 increased (and decrease) cell-cycle activity. Conclusion: ARP1 preserved proliferative capacity of cardiomyocytes located throughout the left ventricle.
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