May 26, 2024

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How does the damaged heart of zebrafish heal itself?

How does the damaged heart of zebrafish heal itself?


How does the damaged heart of zebrafish heal itself? Lrrc10 is indispensable and is also conserved in mammals. 


Following a myocardial infarction, the mammalian heart loses millions of cardiomyocytes ( CMs ) and is replaced by a permanent fibrotic scar.

CM proliferation, observed after cardiac injury in zebrafish, salamanders, and neonatal mammals, is preceded by CM dedifferentiation, which leads to sarcomere disassembly, metabolic reprogramming, and reexpression of embryonic genes.

If this state of dedifferentiation and proliferation persists, it may reduce CM incorporation into the heart and affect cardiac function.

Therefore, there is a need to investigate how the body restores the damaged heart to its original size and maintains normal function.


Recently, the Jeroen Bakkers team from Utrecht University Medical Center in the Netherlands published an article entitled Interplay between calcium and sarcomeres directs cardiomyocyte maturation during regeneration in Science , and they found that the The linked cardiac dyad structure is crucial for the redifferentiation of cardiomyocytes after injury, and its key component Lrrc10 acts as a negative regulator of cardiomyocyte proliferation and can be used to prevent cardiac hypertrophy, and this function is conserved in mammalian cardiomyocytes of .

Taken together, this work underscores the importance of exploiting this mechanism in constructing a functioning regenerative heart.


How does the damaged heart of zebrafish heal itself?



The shuttling of calcium ions between the cytoplasm and sarcoplasmic reticulum in cardiomyocytes is a key step in the realization of cardiac excitation-contraction coupling.

The researchers developed an in vitro imaging system that can observe zebrafish expressing the fluorescent Ca 2+ sensor GCaMP6f to Tracking Ca dynamics during CM regeneration .

The region more distant from the myocardial infarction (RZ) and the adjacent region (BZ, where the CM dedifferentiates and proliferates) exhibited differences in the duration of Ca 2+ influx and efflux at early regeneration stages, whereas BZ-CM Ca 2+ changes were similar to embryonic CM In contrast, early stage Ca influx was not different at each time point, suggesting that BZ-CMs functionally revert to an embryo-like state during early regeneration stages.

Subsequently, the authors performed scRNA-seq analysis on BZ-CMs in the early and late stages of regeneration, and the two stages showed different gene expression characteristics, given that Ca 2+ dynamics are different in the early and late stages and are related to Ca 2+ regulation genes were significantly expressed in late stages, and the authors further screened for candidate genes that might be associated with this state.

A previous population analysis of Mexican cavefish indicated that the lrrc10 (leucine-rich repeat–containing 10) gene was involved in heart regeneration, but the mechanism was unknown [1] .

Interestingly, lrrc10 is down-regulated in the early stage of regeneration and up-regulated in the late stage, so the authors constructed the lrrc10 -/- zebrafish model and found thatlrrc10 -/- CMs were unable to restore their Ca influx and efflux at any stage of regeneration , suggesting a critical role for Lrrc10 in CM maturation.


How does the damaged heart of zebrafish heal itself?Figure 1. Strategies for Monitoring the Ca 2+ Cycle in the Adult Heart .


The cardiac dyad structure enables efficient excitation-contraction coupling through the spatial arrangement of components that regulate Ca2+ flux (L-type calcium channels and sarcoplasmic reticulum) and sarcomeres [2, 3] . Lrrc10 is known to colocalize with dyad components such as α-actinin and RyR2 in mammals , and in zebrafish the authors also found colocalization of lrrc10 with dyad in intact lrrc10 +/+ CM, during regeneration , both lrrc10 +/+ and lrrc10 −/− individuals showed disassembly of α-actinin and L-type calcium channels at an early stage, and at later stages, lrrc10 +/+ BZ-CMs reorganized the dyad assembly comparable to uninjured hearts, Whereas lrrc10 -/- BZ-CM, despite showing sarcomere reorganization, failed to relocate L-type calcium channels to the Z-disk.

The authors wondered whether these changes in damaged hearts could also be observed in mammals. In myocardial infarction mouse hearts, BZ-CMs adjacent to the scar showed complete disassembly of dyad at both early and late stages, and Lrrc10 expression was significantly reduced in BZ-CMs. Similarly, RZ-CMs farther from the infarct site in human MI hearts showed normal assembly of dyads, whereas dyads located in BZ-CMs were disorganized.


How does the damaged heart of zebrafish heal itself?Figure 2. Lrrc10 is required for cardiac dyad formation during regeneration.



CM proliferation is a hallmark of the early regeneration phase, and the peak of proliferation occurred 7 days after injury (7 dpi) , which coincided with the transient peak of lrrc10 expression, however, the authors found that high expression of lrrc10 was inversely correlated with the incorporation of the cell proliferation marker EdU, suggesting that lrrc10 may be a negative regulator of proliferation, and this inhibitory effect is conserved among mammals. Previous work pointed out that the damaged heart can be repaired by inducing CM proliferation by activating specific genes and signaling pathways, but this CM proliferation is often uncontrolled and leads to cardiac hypertrophy [4] .

So could the inhibition of CM proliferation by Lrrc10 be exploited to prevent cardiac hypertrophy? To demonstrate this, the authors overexpressed ca-Vdra in the CM of zebrafish for 6 weeks resulting in cardiac enlargement and marked distension of the chest cavity, whereas zebrafish coexpressing GFP-Lrrc10 showed no signs of cardiac hypertrophy.

Finally, the authors tested whether Lrrc10 could prevent cardiac hypertrophy following CM-specific overexpression of Nrg1.

Zebrafish overexpressing Nrg1 alone exhibited abnormally hypertrophied hearts, while overexpressing GFP-Lrrc10 did not. These data suggest that Lrrc10 is effective in preventing cardiac hypertrophy by inhibiting CM proliferation.


How does the damaged heart of zebrafish heal itself?
Figure 3. Lrrc10 can inhibit CM proliferation and prevent heart enlargement.


Collectively, this work demonstrates a complex and highly correlated role between sarcomeres and Ca2 + regulation during CM maturation through a model of cardiac regeneration in which new CMs are naturally generated, i.e., CMs use Lrrc10 to link sarcomeres and L-type Components of calcium channels bind and recruit to the cardiac dyad region located in the z-disc.

After heart injury, lrrc10 downregulation dedifferentiates BZ-CMs leading to CM proliferation, and upregulation of lrrc10 in newly generated CMs contributes to the reorganization of cardiac dyads, thereby Promotes reconstitution of fully functional mature CMs. These findings demonstrate that cardiac dyads are essential for the CM maturation process.








Original link:


1. WT Stockdale et al., Cell Rep. 25, 1997–2007. e7 (2018)
2. MT Woon et al., J. Am. Heart Assoc . 7, e006428 (2018).
3. W. Feng et al., Circulation 141, 940–942 (2020).
4. M. Ogawa et al., Science 372, 201–205 (2021).

How does the damaged heart of zebrafish heal itself?

(source:internet, reference only)

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