WHAT ARE STEM CELLS?
Stem cells are called “immature” because their main characteristic is that of being able to specialize, in other words, being able to become any tissue and organ of our body. Unfortunately not every tissue of the human body is provided with an area in which stem cells can be produced when we are adults, while at the initial stage of the embryo’s development, all tissue has the ability to produce stem cells. Stem cells can be metaphorically considered “baby cells” that potentially can regenerate countless parts of the body.
WHAT ARE THE DIFFERENT TYPES OF STEM CELLS?
There are 4 different types of stem cells:
- totipotent: they can become any cell of the organism (muscular, nervous, etc.);
- pluripotent: they can evolve in many cell types, but not in all;
- multipotent: they only specialize in a certain type of cell (i.e. nerve cells);
- unipotential: they only generate a certain type of cell (i.e cornea, liver, etc.)
Stem cells are also divided between somatic (improperly called “adult”: they are not yet specialized – they are multipotent – and are generally found among the cells in a specific tissue), and embryonic stem cells (early stages of development following fertilization).
HOW ARE STEM CELLS OBTAINED?
The embryo is the source of stem cells par excellence, but the study and use of embryonic stem cells is restricted for ethical reasons, even in countries where it is permitted. As the embryo develops, its cells specialize and loose their ability to transform into any type of cell. However, if you want to give an unborn child the possibility of having some “spare cells” (such as blood, muscular or nerve cells), there is at least the possibility of storing and preserving them freezing the umbilical cord (although there are a number of limits). Stems cells are also found in the amniotic fluid.
There is also the possibility of obtaining stem cells from adult cells; this technique, developed for the first time in Japan in 2006 (by the Nobel Prize winner for medicine, S.Yamanaka), requires “genetic reprogramming”. Some genes can be used to start a rejuvenation of the adult cell, which returns to the stem stage (as if going back in time); once this rejuvenation is started, the same genes that functioned as a “trigger” are removed from the DNA. Given the complexity of the procedure, some teams of researchers have been able to do without those genes, eliminating the risks associated with their use.
Reprogrammed stem cells (iPS) are pluripotent and represent an important frontier of regenerative medicine. In 2009 the University of Wisconsin-Madison published on PNAS the results of some research, which claimed that it was possible to transform adult skin cells into human retinal stem cells after appropriate genetic reprogramming. In the future, these rejuvenated cells will be able to, at least in principle, be used to repair the retina, which can be affected by degenerative diseases particularly in old age. However, at the time of writing, unfortunately this result has not yet been achieved.
In 2012 the Columbia University (U.S.) published a study in Molecular Medicine in which the researchers claimed to have improved the sight of blind test animals using human skin cells that had been reprogrammed (until they had become retinal stem cells).
In September 2017 an apparently very rigorous Chinese study was published on the use of embryonic stem cells in retinitis pigmentosa patients [Liu Y, Chen SJ, Li SY, Qu LH, Meng XH, Wang Y, Xu HW, Liang ZQ, Yin ZQ, “[Long-term safety of human retinal progenitor cell transplantation in retinitis pigmentosa patients“, Stem Cell Res. Ther. 2017 Sep 29;8(1):209. doi: 10.1186/s13287-017-0661-8]]: the researchers claim to have succeeded, using appropriately treated stem cells conveyed through subretinal injections, to modestly improve their vision in blind mice (genetically modified).
ARE THERE STEM CELLS IN ADULTS?
Yes, stem cells can be obtained from an adult, for example, from the bone marrow (hematopoietic stem cells=blood cell producers), from the adipose tissue (fat) and from a series of specific areas dedicated to the production of stem cells themselves. Regarding the eyes, in particular, on the cornea there is a specific area called limbus (which has the shape of a ring and is located at the border between the transparent front part of the eye, i.e. the cornea, and the white part, i.e. the sclera).
Embryonic stem cells can be obtained by in vitro fertilization in the countries where it is permitted. The problem is that this technique has a precise time limit: up to 5 days from test tube fertilization. Alternatively, in some countries (such as Spain) it is possible to use supernumerary embryos, namely those that are not implanted in the uterus after artificial fertilization. If they are frozen they can “live” for a few years, representing a real stock of embryonic stem cells.
HOW DO STEM CELLS DEVELOP?
Let’s take into consideration the embryonic stem cells that are obtained from a fertilized embryo. These cells can divide and duplicate themselves for a long time, but without differentiation. Therefore, stem cells can generate embryonic germ layers even after being cultured for a virtually indefinite period of time. The 3 types of germ layers originating from stem cells are: ectoderm, mesoderm and endoderm. The ectoderm gives rise not only to the brain, the nerves of the spine and the other nerve cells, but also to the hair, skin and teeth, as well as to the sensory cells of the eye, ear, nose and mouth…The mesoderm, on the other hand, gives rise to the muscles, blood, blood vessels, connective tissue and the heart. Finally the endoderm gives rise to the pancreas, the stomach and the liver, to which the lungs and germ cells (ovules and spermatozoa) should be added.
WHAT POSSIBILITIES DO STEM CELLS OFFER?
On the one hand, it is possible to produce cells and tissues that can be implanted. On the other hand, the study of stem cells makes it possible to better understand the prevention and treatment of genetic disorders. Finally, toxicity tests for some medicines can also be performed more easily. There are many diseases that stem cells can help cure: from Parkinson’s to Alzheimer’s, from heart attacks to retinal damage.
According to the scientific journal Nature, “adult stem cells have already had clinical success, such as in bone-marrow transplantation for leukaemia treatment, growing new skin layers to treat burns and regenerating corneas”. There is also the potential for retinal regeneration, but at present, even in the U.S., it hasn’t been possible to achieve this ambitious result. Treatment proposals without effective scientific validation must never be taken into consideration.
WHAT ARE THE PROSPECTS FOR THE FUTURE?
Stem cells can not only give rise to any type of tissue, but in principle, could also allow us to “manufacture” an entire spare organ, which would not cause any form of rejection, being made of cells from the body of the person receiving it. In theory, many degenerative diseases could be treated in this way one day (potentially even retinal diseases). Stem cells are a virtually unlimited reserve of nerve cells, muscle cells, blood cells, etc.
ARE STEM CELLS A MIRACLE?
Probably, defining stem cells as a miracle today is an exaggeration as their clinical use is still very limited. However, if scientific research were to confirm all expectations, then their use would have really enormous potential, allowing the repair of tissues for which today there is no cure.
However, the British Medical Journal warns against therapies that go beyond official science as well as marketing sites and writes bluntly that “the marketing of unproven stem cell therapies has the potential to harm patients and to harm the reputation of stem cell science”. [Murdoch B, Zarzeczny A, Caulfield T, “[Exploiting science? A systematic analysis of complementary and alternative medicine clinic websites’ marketing of stem cell therapies“, BMJ Open. 2018 Feb 28;8(2):e019414. doi: 10.1136/bmjopen-2017-019414]] So you have to be careful about potential risks and even possible scams.
WHAT ARE THE RISKS?
A possible risk is that a tumour could be induced: the uncontrolled proliferation of stem cells can potentially cause cancer. Furthermore, we have to be careful of stem cells treatments that have not been validated by scientific results. There’s also the risk that reprogrammed adult stem cells may not work exactly like embryonic ones: they are almost the same, but not perfectly identical. For instance, heart cells do not coordinate with each other if they have been induced from adult cells, while their beat occurs in unison if they are developed from embryonic cells.
It cannot be ruled out that an experimental, non-approved stem cells treatment aimed at regenerating the retina, for example, could even cause blindness (this is what happened to three people in the U.S. while an attempt was being made to treat AMD) [Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, Parrott MB, Rosenfeld PJ, Flynn HW Jr, Goldberg JL, “[Vision Loss after Intravitreal Injection of Autologous ‘Stem Cells’ for AMD“, N Engl J Med. 2017, Mar 16;376(11):1047-1053. doi: 10.1056/NEJMoa1609583]], while only in one case in Japan has stabilization been achieved with reprogrammed stem cells (Yamanaka S, Takahashi M et al., NEJM, 2016). At an ophthalmic level, only the use of corneal stem cells to regenerate the eye surface is currently permitted, while worldwide there is still no clinically approved treatment on human beings that leads to the recovery of sight after retinal damage through the use of stem cells.
IN WHICH CASES CAN STEMS CELLS BE USED FOR THE EYES?
At the retinal level the first experiment on human beings was started in Japan in 2014, on a group of six visually impaired people suffering from AMD (the wet form of age-related macular degeneration that reduced their visual acuity to less then 1/10). Researchers had wished to recover about a tenth of the patients’ visual acuity in this way. The experimental protocol, which uses adult cells genetically reprogrammed back to the stem cell stage (iPS), was approved by the Japanese Ministry of Health in July 2013. In the trial, skin cells (fibroblasts) were “rejuvenated” by manipulating their DNA and then developed up to the stage of retinal cells (retinal pigmented epithelium).
However, this approach suffered a setback before the completion of the foreseen 3-year-period: in May 2015 the trial was temporarily suspended at the Riken Research Institute. [Ken Garber, “[RIKEN suspends first clinical trial involving induced pluripotent stem cells“, Nature Biotechnology 33, 890–891 (2015) doi:10.1038/nbt0915-890, Published online 08 September 2015]].
Furthermore, at the time of writing, a study involving people affected by the dry form of AMD and a retinal genetic disease (Stargardt’s maculopathy) is underway in the U.S. This experimental study, carried out using embryonic stem cells, has apparently produced encouraging results (regenerating the retina, at least partially, in more than half of the cases). However, such results have yet to be confirmed and their duration will have to be verified.
HOW DO CORNEAL STEM CELLS WORK?
The corneal limbus (the border of the cornea and the bulbar conjunctiva) is where natural corneal stem cells reside, which serve as a reserve for the regeneration and proliferation of the corneal epithelium. Epithelial stem cells have virtually unlimited potential for cell division. In fact, following stimulus from growth factors, these cells differentiate into ”transit-amplifying cells”, which then replicate and further differentiate until they reach a state of final maturation.
In a healthy subject, it is therefore evident that the presence of efficient stem cells at the corneal limbus level, allows the repair of corneal damage caused by traumatic, infectious and inflammatory phenomena of medium and mild degree. Unfortunately, when a disease or corneal trauma causes an alteration to limbal stem cells leading to a decrease in their number, there is a so-called deficit or limbal insufficiency: as a result, the cornea is no longer able to repair its surface epithelium, which could lead to serious complications that can jeopardize sight. In these cases, great progress has been made by scientific research in recent years: through limbal stem cell transplantations, the corneal epithelium has recovered its ability to regenerate, even if the results are not always satisfactory. However, stem cell transplantation alone does not lead to the recovery of a visual acuity comparable to that prior to trauma, but it is the combination of stem cell transplantation and other surgical procedures (cornea transplantation) that can often give the possibility of improving a patient’s sight, restoring transparency to the damaged cornea.
WHAT ARE THE REAL PERSPECTIVES THAT STEM CELLS OFFER FOR THE RETINA?
It seems that even the adult human retina is endowed with stem cells: extensive research has allowed us to locate these cells in the most peripheral region of the retina itself. In fact, they can be found in the pars plana and pars plicata, where they are present in an indicative measure of one cell for every 500. Retinal stem cells have been identified from the first months after birth to 70 years of age. Even today their field of application is widely experimental, but important studies have been carried out: among other things, attempts have been made to regenerate retinal photoreceptors through their implantation in stem form; however the complexity of the retinal structure and the mechanisms used for vision are obstacles not easily overcome.
In a study published in April 2013 in Cell Research it is claimed that, “multipotent retinal stem cells (RSCs) from the adult mouse retina …] are capable of producing functional photoreceptor cells”, that is to say, they are able to restore sensitivity to light in blind test animals. Another rigorous study on retinal stem cells was published in the journal [The Lancet in October 2014. It stated that visual improvements were found at an experimental level in 10 out of 18 eyes. In this study the subjects were human beings affected by the dry form of age-related macular degeneration (AMD) and Stargardt’s maculopathy. In some of these subjects, the visus improved after 3-12 months from the implantation of human embryonic stem cells.
An experimental project has allowed to obtain encouraging results in London on patients suffering from the AMD exudative form (which apparently did not respond to other therapies) using stem cells. More specifically, Moorfields Eye Hospital wrote, March 19, 2018 – following phase 1 clinical studies of an embryonic stem cell-derived retinal pigment epithelium patch – that “the first patients to receive a new treatment derived from stem cells for people with wet age-related macular degeneration (AMD) have regained reading vision”. The same hospital also writes that “the patients were monitored for 12 months and reported improvements to their vision. They went from not being able to read at all even with glasses, to reading 60-80 words per minute with normal reading glasses” [Read also: da Cruz L, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, Vernon A, Daniels JT, Nommiste B, Hasan SM, Gooljar SB, Carr AF, Vugler A, Ramsden CM, Bictash M, Fenster M, Steer J, Harbinson T, Wilbrey A, Tufail A, Feng G, Whitlock M, Robson AG, Holder GE, Sagoo MS, Loudon PT, Whiting P, Coffey PJ, “[Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration“, Nat Biotechnol. 2018 Apr;36(4):328-337. doi: 10.1038/nbt.4114. Epub 2018 Mar 19]].
In the conclusion of an article published in the American Journal of Ophthalmology in 2017 (Rao, Rajesh C. et al., “Stem cells for retinal disease: a perspective on the promise and perils“), however it is stated:
Stem/progenitor cell-based interventions have the potential to address blinding retinal diseases that affect hundreds of millions worldwide. Yet no Food and Drug Administration-approved stem cell therapies for retinal disease exist. Although some early-phase trial data are promising, reports of blinding complications from cell interventions remain troubling.
Therefore it will be necessary to ensure that these treatments don’t cause any harm to human health, possibly by developing, in the future, safe and effective therapies.
Researchers in the U.S. are currently carrying out the largest official experiment on stem cells that are being used to treat several pathologies and ocular traumas (affecting the retina and/or the optic nerve): it involves 500 people and, after starting in 2016, will continue until at least 2021. This vast sponsored research uses human stem cells taken from bone marrow. According to some studies that have already been published during the trial, there have been positive results in some patients, but this must be confirmed by further research.
WHAT CAN WE REALLY HOPE FOR?
The hope is that, at least in the future, stem cells can be used to treat several degenerative diseases that, at present, are some of the main causes of blindness (retinitis pigmentosa, age-related macular degeneration, etc.). In the case of genetic degenerative diseases, great potential is given to the combined use of gene therapy (injection of the correct gene under the retina) and stem cells (for example reprogrammed adult ones).
John Gurdon, who won the Nobel Prize for medicine in 2012, said that “there are very solid perspectives” for the treatment of retinal degeneration with adult stem cells. However, it will be necessary to wait for further studies to be carried out, before a large-scale clinical application is possible, provided that all the phases of the experiments on human beings are successful.
Read also (it. version): “Vista salvata con le staminali”, “Staminali riprogrammate contro la cecità”, “Usa, rigenerata la retina centrale con staminali embrionali”
To deepen: consult the website of the Italian Society of Ophthalmology (SOI).
Sitegraphy and bibliography
- “Stem Cells Improve Visual Function in Blind Mice“, Columbia University, 13 settembre 2012. Original scientific study: Li Y, Tsai YT, Hsu CW, Erol D, Yang J, Wu WH, Davis RJ, Egli D, Tsang SH, “Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa“, Molecular Medicine 2012 Dec 6;18:1312-9. doi: 10.2119/molmed.2012.00242
- Jason S. Meyer, Rebecca L. Shearer, Elizabeth E. Capowski, Lynda S. Wright, Kyle A. Wallace, Erin L. McMillan, Su-Chun Zhang, David M. Gamm, “Modeling early retinal development with human embryonic and induced pluripotent stem cells“, PNAS 2009 106 (39) 16698-16703; published ahead of print August 25, 2009, doi:10.1073/pnas.0905245106
- Coles BL, Angénieux B, Inoue T, Del Rio-Tsonis K, Spence JR, McInnes RR, Arsenijevic Y, van der Kooy D., “Facile isolation and the characterization of human retinal stem cells“, Proc Natl Acad Sci U S A., Nov 2;101(44):15772-7. Epub 2004 Oct 25
- Singh MS, Charbel Issa P, Butler R, Martin C, Lipinski DM, Sekaran S, Barnard AR, MacLaren RE., “Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation“, Proc Natl Acad Sci U S A. 2013 Jan 15;110(3):1101-6. doi: 10.1073/pnas.1119416110. Epub 2013 Jan 3
- Li T, Lewallen M, Chen S, Yu W, Zhang N, Xie T., “Multipotent stem cells isolated from the adult mouse retina are capable of producing functional photoreceptor cells“, Cell Res. 2013 Apr 9. doi: 10.1038/cr.2013.48 [Epub ahead of print]
- “Smoke and Mirrors” (Editorial), Nature, Volume: 496, pp. 269–270, 18 April 2013, DOI: doi:10.1038/496269b
- “Pilot clinical study into iPS cell therapy for eye disease starts in Japan“, July 30, 2013, Riken
- “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies“, Prof Steven D Schwartz MD,Prof Carl D Regillo MD,Prof Byron L Lam MD,Dean Eliott MD,Prof Philip J Rosenfeld MD,Ninel Z Gregori MD,Jean-Pierre Hubschman MD,Prof Janet L Davis MD,Gad Heilwell MD,Marc Spirn MD,Joseph Maguire MD,Roger Gay PhD,Jane Bateman RN,Rosaleen M Ostrick MPH,Debra Morris MPH,Matthew Vincent PhD,Eddy Anglade MD,Prof Lucian V Del Priore MD,Prof Robert Lanza MD, The Lancet, 15 October 2014, DOI: 10.1016/S0140-6736(14)61376-3
- “First patient receives potential new treatment for wet age-related macular degeneration in London Project to Cure Blindness“, The London Project to Cure Blindness, 28 September 2015
- Rao, Rajesh C. et al., “Stem cells for retinal disease: a perspective on the promise and perils”, American Journal of Ophthalmology, April 17, 2017
- “One stem cell treatment stabilizes macular degeneration, another blinds 3 patients” (CNN), March 16, 2017
- Yamanaka S, Takahashi M et al., “Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration“, N Engl J Med. 2017 Mar 16;376(11):1038-1046. doi: 10.1056/NEJMoa1608368.
- Clinical Trials.gov (NIH, Usa)
- Sharma R, Khristov V, Rising A, Jha BS, Dejene R, Hotaling N, Li Y, Stoddard J, Stankewicz C, Wan Q, Zhang C, Campos MM, Miyagishima KJ, McGaughey D, Villasmil R, Mattapallil M, Stanzel B, Qian H, Wong W, Chase L, Charles S, McGill T, Miller S, Maminishkis A, Amaral J, Bharti K, “Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs”, Sci Transl Med. 2019 Jan 16;11(475). pii: eaat5580. doi: 10.1126/scitranslmed.aat5580.