The Role of Immune Cells in Enhanced Regeneration of Organs

Immune cells play an important role in regeneration, though this is yet another aspect of the immune system as a whole that is understood in outline but the all-important details remain a big blank space in the middle of the map. The interactions between the immune system and the rest of our biochemistry are very complex, to say the least, and cataloging them will no doubt keep hundreds of researchers busy for a few decades yet. There are many good reasons to dig into these details, and one of them is that immune cells and their behavior may have a lot to do with the very large differences in regenerative capabilities observed both between species and between embryonic and adult regeneration in the same species. It is quite possible that enhanced regeneration of organs in mammals might be obtained through nothing more than manipulation of immune cells, though it remains to be seen just how far this approach can take us.

Salamanders and zebrafish are both studied for their ability to regenerate entire organs, such as the heart and limbs. In both cases, the immune cells called macrophages have been shown to play a necessary role in this exceptional regeneration. Without them, lost tissue scars as it does in mammals rather than regenerating to form new replacement tissue structures. Some mammals have demonstrated enhanced regeneration with similarities to salamander regeneration, however, such as the genetically engineered MRL mice that lack the p21 gene. Given the connections between the immune system and tissue regrowth it is tempting to speculate on whether enhanced regeneration in the MRL mouse lineage has anything to do with p21's immune regulation roles. Sadly there is still too little data here to do more than speculate.

Below you'll find a more recent study that demonstrates immune cells to be responsible for a portion of the differences between mammalian embryonic and adult heart tissue regeneration. As you might be aware, the heart doesn't regenerate well at all in adults, but it's a whole different story in embryos. That's true for a range of tissues, in fact, but this work just covers the heart:

Heart's own immune cells can help it heal

The heart holds its own pool of immune cells capable of helping it heal after injury. Most of the time when the heart is injured, these beneficial immune cells are supplanted by immune cells from the bone marrow, which are spurred to converge in the heart and cause inflammation that leads to further damage. In both cases, these immune cells are called macrophages, whether they reside in the heart or arrive from the bone marrow. Although they share a name, where they originate appears to determine whether they are helpful are harmful to an injured heart. In a mouse model of heart failure, blocking the bone marrow's macrophages from entering the heart protects the organ's beneficial pool of macrophages, allowing them to remain in the heart, where they promote regeneration and recovery.

Researchers have known for a long time that the neonatal mouse heart can recover well from injury, and in some cases can even regenerate. If you cut off the lower tip of the neonatal mouse heart, it can grow back. But if you do the same thing to an adult mouse heart, it forms scar tissue. This disparity in healing capacity was long a mystery because the same immune cells appeared responsible for both repair and damage. Until recently, it was impossible to distinguish the helpful macrophages that reside in the heart from the harmful ones that arrive from the bone marrow.

The investigators found that the helpful macrophages originate in the embryonic heart and harmful macrophages originate in the bone marrow and could be distinguished by whether they express a protein on their surface called CCR2. Macrophages without CCR2 originate in the heart; those with CCR2 come from the bone marrow, the research showed. [The researchers] asked whether a compound that inhibits the CCR2 protein would block the bone marrow's macrophages from entering the heart. "When we did that, we found that the macrophages from the bone marrow did not come in. And the macrophages native to the heart remained. We saw reduced inflammation in these injured adult hearts, less oxidative damage and improved repair. We also saw new blood vessel growth. By blocking the CCR2 signaling, we were able to keep the resident macrophages around and promote repair. We have identified similar immune cell subtypes that are present in the human heart. We need to find out more about their roles in heart failure in patients and understand more about how macrophages that reside in the heart promote repair."


Hmm, I'm curious:

If it _is_ the case that macrophages originating in bone marrow harm the heart while those originating in the heart are quite helpful...

...why do bone marrow macrophages get sent to the heart in the first place?

(i.e. What are the mechanisms in the body that cause that, and why are those mechanisms there?)

Posted by: Xin at November 2nd, 2014 9:12 PM
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