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Several people ask me interesting Qs on regeneration. They read about lost or amputated  limbs. They wonder whether science can help these unfortunate human beings. Several Qs arise from these tormented minds. Let me answer one such Q.

Q: How can some reptiles like Lizards, gecko and salamander regrow their limbs? Why are humans not able to fully understand this process and replicate?
Krishna: A particular field of biology studies animals that are actually capable of regenerating severed parts of their bodies: regeneration biology. By studying salamanders, lizards, and flatworms, (1,2,3)the

scientists look at the mechanisms these animals use to regenerate lost body parts, in the hope that one day humans could too. 
The process these animals use are actually well-documented. When there is a wound, the outermost layer of skin covers up this wound. A bump then appears, called the wound epidermis. It sends instructions to cells near and beneath it and mature cells become immature ones called blastema. And then Nerve cells start to regenerate.

The blastema is key to regeneration. Those immature cells start dividing and differentiating into the cells of the lost limb. The cells that form the blastema are stem cells, cells that have not differentiated into a final cell type. There is also some form of memory that tells the process when to stop, with the blastema only regenerating the lost hand or leg, no more.

This process can be slow. A 4 mm (.16 inches) limb can take as much as 400 days to grow back. What of something as large as an adult arm? Years? Decades?  Human cells don't regenerate as well as some animal cells because of the fact that humans have more complex cells than some animals.

There are several theories regarding why humans can't regenerate like some animals do.

One theory suggests that scar tissue is an adaptation — but one that prevents regeneration. Scar tissue forms quickly and helps seal over a wound, but it’s made of different materials than unmarred skin, and it’s fast and quick, but not performing at the same standard.

Another theory is that the cellular machinery that triggered regeneration was lost, possibly because the growth of cells can look a lot like cancer. Better to prevent growth (that could possibly get out of control) than to risk the development of a cancerous tumour.

We may also not have enough stem cells, or our cells have lost the capacity to naturally regress back to an undifferentiated state. Again, stem cells tend to pop up in cancerous tumours, so this loss isn’t necessarily a bad thing for us.

Finally, some of the challenge may be increased complexity — a human limb is more complex than that of a salamander. That may pose a challenge for regrowth.

Regeneration means the regrowth of a damaged or missing organ part or lost tissues in response to injury from the remaining tissue. As adults, humans can regenerate some organs, such as the liver. If part of the liver is lost by disease or injury, the liver grows back to its original size, though not its original shape. And our skin is constantly being renewed and repaired. Unfortunately many other human tissues don’t regenerate, and a goal in regenerative medicine is to find ways to kick-start tissue regeneration in the body, or to engineer replacement tissues.

There are now several human tissues that have been successfully or partially induced to regenerate. Many of these examples fall under the topic of regenerative medicine, which includes the methods and research conducted with the aim of regenerating the organs and tissues of humans as a result of injury. The major strategies of regenerative medicine include dedifferentiating injury site cells, transplanting stem cells, implanting lab-grown tissues and organs, and implanting bioartificial tissues. 

 In 1999 the bladder was the first regenerated organ to be given to seven patients; as of 2014, these regenerated bladders are still functioning inside the beneficiaries(4).

Researchers are very interested in understanding what signals turn stem cells ‘on’ when regeneration is needed, and keep them ‘off’ when they’re not needed.

Numerous tissues and organs have been induced to regenerate. Bladders have been 3d printed in the lab since 1999. Skin tissue can be regenerated in vivo, and in vitro. Other organs and body parts that have been procured to regenerate include: penis, fats, vagina, brain tissue, thymus, and a scaled down human heart. Ongoing research, aims to induce full regeneration in more human organs.

Certain human body parts can 'regenerate naturally'.  For instance, Cardiomyocyte necrosis activates an inflammatory response that serves to clear the injured myocardium from dead cells, and stimulates repair, but may also extend injury. Research suggests that the cell types involved in the process play an important role. Namely monocyte-derived macrophages tend to induce inflammation while inhibiting cardiac regeneration, while tissue resident macrophages may help restoration of tissue structure and function (5).

The endometrium after the process of breakdown via the menstruation cycle, re-epithelializes swiftly and regenerates.
There are reports of adult digital tip regeneration (6,7).Studies in the 1970s showed that children up to the age of 10 or so who lose fingertips in accidents can regrow the tip of the digit within a month provided their wounds are not sealed up with flaps of skin – the de facto treatment in such emergencies. They normally won't have a fingerprint, and if there is any piece of the finger nail left it will grow back as well, usually in a square shape rather than round (8,9).

Similarly in the mammalian kidney, the regeneration of the tubular component following an acute injury is well known. Recently regeneration of the glomerulus has also been documented (10).

In 1999 the bladder was the first regenerated organ to be given to seven patients (4). The penis has been successfully regenerated in the lab (12).

It has been shown that bone marrow-derived cells could be the source of progenitor cells of multiple cell lineages, and a 2004 study suggested that one of these cell types was involved in lung regeneration (11). 

Spinal chord nerves have also been regenerated, reconnecting damaged neural circuits by injecting  stem cells, in vivo, into the site of the  injury. A Patient eventually gained feeling, movement and sensation in his limbs, especially on the side where the stem cells were injected; he also reported gaining sexual function. He can now drive and can now walk some distance aided by a frame (13, 14).

 The thymus gland is one of the first organs to degenerate in normal healthy individuals (15).

 Researchers are, of course, searching for ways to encourage more regeneration in humans. However, given the immense complexity of the task, such a process will likely be slow and made through many gradual breakthroughs, rather than being a single solution away from happening.

We can create new adult stem cells, but it’s going to be a lot more work before we can encourage those cells to grow into a new limb.

As always, I would say funding is the main issue for this field not developing as it should really do.

Science is a very slow process and takes years and years of research for making progress. 

And as soon as these problems are sorted out, human organ regeneration too becomes a reality.


Footnotes:

1. Regeneration of Limb Joints in the Axolotl (Ambystoma mexicanum)
4. Mohammadi, Dara (4 October 2014). "Bioengineered organs: The story so far…"theguardian.com. Retrieved 9 March 2015.
5. Frangogiannis, N.G. (May 2015). "Inflammation in cardiac injury, repair and regeneration"Curr Opin Cardiol30 (3): 240–245. doi:10.1097/HCO.0000000000000158PMC 4401066PMID 25807226

6. McKim, L.H. (May 1932). "Regeneration Of The Distal Phalanx". The Canadian Medical Association Journal. 26 (5): 549–550. PMC 402335. PMID 20318716.
7. Wicker, Jordan; Kenneth Kamler (August 2009). "Current concepts in limb regeneration: A hand surgeon's perspective". Annals of the New York Academy of Sciences. 1172 (1): 95–109. Bibcode:2009NYASA1172...95W. doi:10.1111/j.1749-6632.2009.04413.x. PMID 19735243.
8. Weintraub, Arlene (May 24, 2004). "The Geniuses Of Regeneration". BusinessWeek.
9. Illingworth Cynthia M (1974). "Trapped fingers and amputated fingertips in children". Journal of Pediatric Surgery. 9 (6): 853–858. doi:10.1016/s0022-3468(74)80220-4. PMID 4473530.

10. Song Jeremy J (2013). "Regeneration and experimental orthotopic transplantation of a bioe...Nature Medicine19 (5): 646–651. doi:10.1038/nm.3154PMC 3650107PMID 23584091.

11.  Ishizawa K, et al. (2004). "Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysemal". FEBS. 556 (1–3): 249–252. doi:10.1016/s0014-5793(03)01399-1PMID 14706858S2CID 1334711.

12. Mohammadi, Dara (4 October 2014). "Bioengineered organs: The story so far…". theguardian.com. Retrieved 9 March 2015.

13. Quinn, Ben (21 October 2014). "Paralysed man Darek Fidyka walks again after pioneering surgery". The Guardian. Retrieved 26 October 2014. The 38-year-old, who is believed to be the first person in the world to recover from complete severing of the spinal nerves, can now walk with a frame and has been able to resume an independent life, even to the extent of driving a car, while sensation has returned to his lower limbs.

14.Walsh, Fergus (21 October 2014). "Paralysed man walks again after cell transplant". BBC. Retrieved 26 October 2014.

15. Blackburn, CC (April 2014). "Regeneration of the aged thymus by a single transcription factor"Development141 (8): 1627–1637. doi:10.1242/dev.103614PMC 3978836PMID 24715454.

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18

It Turns Out Alligators Can Regrow Their Tails Too

Small reptiles such as geckos and skinks are well known for this remarkable ability to sacrifice and then rapidly regrow their tails. Now, to scientists' surprise, it turns out that much larger alligators can regrow theirs too. But only while they're young.

Juvenile American alligators (Alligator mississippiensis) can regrow up to 18 percent of their total body length back. This is about 23 cm or 9 inches of length.

What's really cool is this regrowth appears to occur via a mechanism we've not seen before.

By imaging and dissecting the tail regrowth, researchers found alligators do this quite differently from the other animals we know that can regenerate their appendages.

As far as regrowing body parts goes, amphibious axolotls are the champions of regeneration amongst land animals with internal skeletons.

If injured, they can reform a segmented skeleton, complete with muscles that differ along their height - distinguishing top from bottom.

Regrown lizard tails do not have a segmented skeleton, but lizards do reform muscles - although they look uniformly the same, with no variation in topside structure compared to the bottom.

This may be because regenerating appendages is physiologically expensive, and in smaller lizards has been shown to reduce overall growth rate.

Alligators, it seems, don't even bother re-growing muscles at all. Clearly there is a high cost to producing new muscle.

The research team thinks that even a muscle-less extra bit of tail must give these dangerous predators an edge in their murkily watered homes.

Unlike lizards, they can't self-amputate - their tail loss usually results from trauma inflicted by territorial aggression, or cannibalism from larger individuals.

Damage from human interactions, like motor blade damage have also been recorded.

Regrown tails from juvenile American alligators exhibit features of both regeneration and wound repair.

https://www.nature.com/articles/s41598-020-77052-8

https://www.sciencealert.com/it-s-not-just-little-lizards-young-all...

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