Regenerative medicine - what can and cannot be replaced in the human body?

Highlights:

• Regeneration is a natural property and salamanders are a model organism for regeneration studies 
• The ongoing research in regenerative medicine includes the induced pluripotent stem cells (iPSC), 3D bioprinting or tooth enamel regeneration

Introduction

Throughout the history of medicine, very little could be done to restore structures in tissues that had been damaged. From a physician's perspective, very few diseases can be cured if one defines cures as not only managing but getting the disease removed from the body. This is eventually going to change, though, as the field of regenerative medicine has continued to advance for decades.

The only diseases that can be fully cured pharmaceutically are cancer (chemotherapy) and infectious diseases that can be treated by antivirals, antibiotics, antifungal agents, and others. In these cases, when a bacteria is gone from the body or cancer cells have been eliminated, one can say that a patient has been cured. However, there is no way to, for example, restore a heart that has been damaged after a heart attack by getting rid of the scar tissue (fibrosis) and regenerating perfectly functional cardiac tissue back. There is no cure for most diseases of old age since there has been no way to remove the damage aging causes. Furthermore, no treatment can regenerate burn injuries or regrow a lost limb to restore the original state.

The field of regenerative medicine encompasses multiple approaches, harnessing the body's repair processes to trigger the restoration of tissue and injecting, e.g., stem cells that have been taken from either the patient's body or other sources. The area of research also covers transplantation of fully lab-grown organs, which could end the organ shortage that currently exists and is a significant challenge for health care. The field of regenerative medicine would open up endless possibilities for the restoration of health in an unprecedented way.

Regeneration: Properties of nature

In nature, there are many models to study regenerative properties. For example, salamanders can grow back limbs that have been cut off and they do not form scar tissues like in humans (1).

Humans have increased regenerative abilities early in life. In the womb, injuries heal easier than later, and during the first few months of a child's life, the tip of the fingers can still regenerate if being cut off (2). During evolution, there has been no pressure to create perfect regeneration in humans since the species have not lived long enough, and that is why we have aged in the first place. This can also be seen in the example of injuries. An injury that heals fast but produces scar tissue is more efficient than a perfect repair. If, for example, a cut would heal perfectly without a scar, it would take much longer time which in nature would mean going around with a wound for longer. This would be a dangerous strategy since it would mean a higher risk of a lethal infection and subsequent death, so the evolutionary way of solving this was to have a quick but imperfect repair (3).

With aging, even in the absence of exterior injury, the organs undergo fibrosis which means a buildup of scar-like tissue impairing their functionality. Age-related fibrosis is especially prevalent in the lungs, heart, and kidneys, where functionality declines with age (4).

Ongoing research

While the regenerative capacities of the human body are limited, there is a wide range of research ongoing within the field. Regenerative medicine has primarily focused on areas such as induced pluripotent stem cells, bioprinting of organs and tissues, the scaffolding of organs, endogenous regeneration, and MedTech to replace tissue artificially.

The induced pluripotent stem cells (iPSC) area represents a significant branch where cells are taken out of the human body and reprogrammed to an embryonic state where they can differentiate into multiple tissues. These can then be coaxed into forming many types of cells for the desired location of injection. Researchers on iPSCs are trying it for diseases such as heart attacks to restore cardiac pump capacity, beta cells transplants to treat diabetes, and neuronal repopulation in the brain's substantia nigra region to treat Parkinson's with varying degrees of results (5).

Bioprinting serves to replicate organs by using 3D printers with seeded cells that can recreate simple structures. The goal is to reach the point of whole organs eventually. Bioprinting is used to create organoids that researchers may use in the lab to simulate real organs, but it is still not a method to solve the problem of organ shortage. Scaffolding means using tissue engineering to regrow organs based on using a structure that mimics the natural organ to form a structure. Endogenous regeneration means using drugs to activate the self-repairing mechanisms of the body without artificially inserting cells, which can be done through different growth factors (6).

Another area that is on the verge of implementation is the regeneration of tooth enamel. With age and a diet rich in fizzy drinks, the enamel is slowly eroded in a large majority of adults. The enamel is formed in the embryonic state and does not regenerate after birth but forms a protective layer of dead tissue. One can use scaffolding biomaterials to trigger the regeneration of this layer which can be used to restore older adults' teeth back to the thick white layer of young adults. This has cosmetic benefits and can also protect against cavities and help in diseases where lack of enamel is an issue (8).

Despite all these available methods, the field faces many challenges, for example, recreating complex tissue structures and blood vessels. In addition, it is important to prevent undifferentiated cells from being left behind in the tissue since these could cause teratomas.

The only stem cell therapies by the FDA currently are hematopoietic stem cells used to treat leukemia. However, stem cell research is done for many purposes despite having a long way to go to safe clinical translation in a patient (7).

To circumvent regulations regarding stem cell research, there are many offshore clinics where stem cell injections are administered to people paying, and often these have a reputation of not adhering to scientific rigor. On top of that, the word "stem cell research" is often used for pseudoscientific purposes, such as creams containing stem cells that do not influence anything in the human body. The area is also subject to public scrutiny due to deaths related to the area's experimental stage. The field of regenerative medicine has been criticized in cases of outright malpractice that have been featured in the media, such as the failed lab-engineered tracheas by Dr. Paolo Macchiarini.

Future

The field of regenerative medicine may be facing many challenges but will eventually be a significantly important aspect of rejuvenation. Apart from clearing damage from the aging body (such as misfolded protein aggregates and senescent cells), regenerative medicine is necessary to replace lost structures. For example, exhaustion of stem cells occurs with age and contributes to immune system failure and sarcopenia. Replenishing this loss as well as reactivating dormant cell production would be necessary to live longer than currently. In cases of extremely long living people there is a tendency of clonality of white blood cells which contributes to immunosenescence and subsequent risk of death from infection.

1. Joven A, Elewa A, Simon A. Model systems for regeneration: salamanders. Development. 2019;146(14):dev167700. Published 2019 Jul 22. doi:10.1242/dev.167700
2. Shieh SJ, Cheng TC. Regeneration and repair of human digits and limbs: fact and fiction. Regeneration (Oxf). 2015;2(4):149-168. Published 2015 Oct 13. doi:10.1002/reg2.41
3. Harty M, Neff AW, King MW, Mescher AL. Regeneration or scarring: an immunologic perspective. Dev Dyn. 2003 Feb;226(2):268-79. doi: 10.1002/dvdy.10239. PMID: 12557205.
4. Murtha LA, Morten M, Schuliga MJ, et al. The Role of Pathological Aging in Cardiac and Pulmonary Fibrosis. Aging Dis. 2019;10(2):419-428. Published 2019 Apr 1. doi:10.14336/AD.2018.0601
5. Singh VK, Kalsan M, Kumar N, Saini A, Chandra R. Induced pluripotent stem cells: applications in regenerative medicine, disease modeling, and drug discovery. Front Cell Dev Biol. 2015;3:2. Published 2015 Feb 2. doi:10.3389/fcell.2015.00002
6. Wells, J.M., Watt, F.M. Diverse mechanisms for endogenous regeneration and repair in mammalian organs. Nature 557, 322–328 (2018).
7. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006 Apr 27;354(17):1813-26. doi: 10.1056/NEJMra052638. PMID: 16641398.
8. Pandya M, Diekwisch TGH. Enamel biomimetics-fiction or future of dentistry. Int J Oral Sci. 2019;11(1):8. Published 2019 Jan 5. doi:10.1038/s41368-018-0038-6

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