Stem Cell Therapy - Gate to Immortality

The Medical Knowledge - The Current Source of Knowledge

Novel knowledge constitutes of awaited news in some nations, a grace in others, and a challenging assignment or commission in some countries. After adequate analysis, the reaction to innovation may be perceived by an individual in its extremes. It is seen as a welcoming solution or as an unwanted problem. In our daily medical practice, news reaches practitioners in two different main ways; the professional and unprofessional path, but more precisely by the following means:

1. Via new released books:

This tool is highly professional but becoming difficult when a practitioner develops a busy occupational life. Physicians rarely visit libraries for continuous medical education in most of systems around the world.

2. Via national and international, academic and non-academic conferences, lectures and seminars:

This way is still the most popular and considered by many a resourceful way, where physicians find out a relaxing time mixing the pleasure with some learning. The learning process can be passive and incomplete and needs complementary work.

3. Via medical representative office visits:

Surprisingly, physicians claim this way to be intensely present on a monthly or even weekly basis, especially for those who are too busy with work, less social, or do not go out on a national level or travel. Physicians discover new information after conversation with a company representative; whatsoever they must complement it with a scientific search.

4. Via internet:

Internet is a great tool, misused by some and well-used by others. Unless there is no referral to a concrete theme, it is quite hard for a physician to be updated with the latest in medical sciences.

5. Via a colleague in the medical field:

A conversation between two professionals can lead to a fruitful knowledge transmission. This transmission is characterized by trust and a rapid use of the transmitted knowledge.

6. Via the patient’s family:

Whatever the criticism of this method is, we cannot hide that many physicians hear first about a new treatment from the visiting patient’s family or from the patient himself.

The Medical Knowledge - The Effect of Occupation on News Acceptance

Culture can influence one’s life; it has a direct inspiration on daily thinking and accordingly life management. During the process of practicing, a physician continues to receive new information. Regardless to his learning curve, his learning process doesn’t end, unlike many other professions. There is a remaining question: will a physician really accept all the newly captured knowledge?

For a physician, it is not such plain and smooth, after hard learning through the most difficult years, to passively receive more knowledge, digest it, and involve it into his own practice as simple as new material. The more he has had hard times during his academic years, the more he will become attached to the traditional fulfillments.

The new data should frequently pass through analysis which a physician often does personally and sometimes collectively. This mentioned analysis is not only scientific, but it is also economic looking to the intruded element in a 360 degrees style.

Accordingly, his studying comprises effect of the introduced knowledge on his carrier, subsequently, a very big “chunk” of knowledge which can surely impact his profession, will definitely not pass without a firm testing.

The majority of small news has a small effect on a physician’s daily life and profession if we omit the word business, but a big chunk can definitely be life reforming at the occupational level.


The Medical Knowledge - Rejection of New Knowledge

As I mentioned in the previous paragraph, a "test" should be done. But is it efficient to do tests on all novelties in medicine? In the physicians' schema, there is a simple policy of refusal, facilitating the filtration of news minimizing the potential damage, and it is generally based on a series of practical questions, answers, and subjection dictating the act of rejection:


Argue 1: The Pseudo-science

A physician thinks: "As long as this data was not given during the study time at the university, I assume it is questionable".
Physicians are a group of professionals who do not question the anatomy of an arterial variant or the side effect of a pharmacological substance during their academic years, but once they act on their own, they become very critical to issues which may remodel their work and disturb its harmony.


Argue 2: The Popularity

A physician analyzes: "Why is this technique known in unpopular country like the Philippines (or Lebanon, or Albania, or Malta)? Maybe something mistaken is around?"

Rich and militarily strong countries are popular to be the most scientific. It looks somehow peculiar but this is the reality of medicine. Physicians rarely "respect" unpopular countries' knowledge or inventions, unless this knowledge is "packaged and advertised" by a first world country.

For a better understanding of this point, we must know that a strong country never declares: "I am the strongest; you must consider me the smartest." … But the third world country considers itself behind seeing the tiny fund dedicated to their field of science compared to the huge fund of the rich countries.


Argue 3: Sticking to evidence

A physician's regular behavior towards new knowledge can also take this statement: "Why should I accept when everyone around me is refusing?"

This question is always present, and a physician directs it towards himself. The PET-scan is an example of this type of subjection; the positron emission tomography machine marked itself in history of biotechnology and reminded the medical society of how tough the process was of introducing its technology.

Without going into political or economic causes, I summarize that almost 50 years after its invention, the PET scan received a legal approval for use, and one of the factors most responsible for the acceptance of positron imaging is the development of radio-pharmaceuticals, which is the material needed to get images captured from active sites from inside the human body.

Moreover, in their economical article, Ido et al (1978) admit that the development of labeled 2-fluorodeoxy-D-glucose (2FDG) by the Brookhaven group under the direction of Al Wolf and Joanna Fowler was a major factor in expanding the scope of PET imaging. Pointing to this fact has no advertising purposes.


Argue 4: The mass effect

Influence and pressure of the government and colleagues can sometimes be misleading. "Our government is not allowing it so there is something wrong with it". We can commonly hear this phrase. This is when personal judgment is not acting, but just in a minimal degree and includes a subconscious rejection.

It may seem to us that scientific proof in clinical trials are sufficient tools for a drug or medical procedure to be used… but the truth is sadly different. In 2011, Ananda Krishna et al.concluded in their PubMed publication "Myocardial Infarction and Stem Cells" that when they were talking about treatment of cardiac infarct with a diversity of types of stem cells in multiple clinical studies "These clinical studies have demonstrated a good safety profile, improvedcardiac function, and favorable effects in patients with MI.

The results obtained from animal studies are promising, and the data obtained from the human clinical trials are even more encouraging." As we can expect, this treatment is still inexistent till date of this manuscript.


Argue 5: The holistic impact on medical economy

A practitioner's thinks: "I should refuse because of its negative impact on my business; I don't have gain and I even may be losing money if I use it".

Starting with a practical look at this point in a diagnostic clinic, there is a remarkable difference between the series genetic tests and the series of markers tests. Someone can prudently listen to the physician telling his patient during the process of prescribing these exams that a positive genetic test does not mean you have the disease or that you will develop the disease, but when it comes to a positive result of a biological marker or a tumor marker, you hear the physician talking about the necessity of acting fast.

Obviously, a biological marker is not only more crucial, but also more useful in the medical field than a genetic test on the daily level, but both tests are prescribed with the same "desire". In this considered case of investigations, it's not about prevention or screening parameters, it's about the concept of diagnosis itself.

When it comes to practice, both tests massively invaded the market because they had similar economic value, and they were presented with a vast financial gain, regardless to the individual gain and scientific aim. Similarly, vaccination changed the face of medicine, immunohistochemistry at a good extent too, where chemotherapy was defended like antibiotics in the past and now still for its 40th year in a row for a clearly controversial remedial effect and an over-prescription rate.


Argue 6: Politics

It is not a secret to anyone that brain drainage is happening all over the world, even between institutions in the same country. This is based on "We are the inventors.", and this is how universities achieve more credibility and become that supreme institution of science. But unfortunately, this fact is extending to "I used to be the inventor, so if I am not, I can lead theadvancement of this invention", and this fact is still acceptable till such proclamations like theseones come to life: "I refuse; I am not the inventor", or "If I am not involved in the core, I will reject". This can be named the "scientific dictatorship".

Sometimes the politics exert a negative role over the scientist leading him to think: "Why am I still so behind?", and at the end some researchers are "extremely" determinate persons.
Consequently, deceived researchers may not hide the information, but they just don't focus on the new field, having no bad intention to mislead the public opinion.


The Medical Knowledge - Complexity of the Globalism

In his article "Cultures and Organizations: Software of the mind" Hofstede defined in 1997 "Culture refers to the cumulative deposit of knowledge, experience, beliefs, values,attitudes, meanings, hierarchies, religion, notions of time, roles, spatial relations, concepts of the universe, and material objects and possessions acquired by a group of people in the course of generations through individual and group striving" In Cultures and Organizations: Software of the mind.

He continued, "People even within the same culture carry several layers of mental programming", and he stated 6 levels of mental programming:

1. The gender level

2. The social class level: related to education and occupation

3. The generation level

4. The regional level: based on ethnicity, language, religions within a nation

5. The national level

6. The corporate level: Associated with the particular culture of a group of employed people

The above review was to enhance mentioned features of that cumulative deposit of knowledge, beliefs, religion, and finding the ultimate norms that satisfies the complex cultural puzzle is difficult.

In the Viewpoint Innovation featured in Aberdeen Press & Journal on the 1st of April 2011 under Individualism versus Communitarianism, we see how the education system in western countries is based on individualism rather than communitarianism.

Student independence is expected, a teacher can provide essential guidance and collaboration between students, and work or idea copying is not expected. Students coming from community oriented cultures will wait for their teacher to be supportive or may hesitate to participate if they are not used to doing so. However, they may be marked down due to lack of participation.

Learning styles can be influenced by culture where certain cultures may learn best by observing and then doing. Some need assistance for the first time, others prefer verbal instructions, and some prefer visual instructions.

However, it could be that these last ones come from cultures where they learn by watching their parents or teachers doing the task first before they try it themselves. Therefore, the different learning styles can be:

• Show me and I'll learn

• Tell me and I'll learn

• Give me the instructions to read, and I'll learn

In countries like Lebanon, where the culture of people has emerged from various civilizations over thousands of years, we undoubtedly meet the diverse ethnicity of our spot eliciting a "décalage" (French), a clash of acquaintance, induced by the different genes of ancestors.

The magic of the communication is not new. The historical role of the Mediterranean sailors, and the Persian and Assyrian traders, and later the role of Arabs in importing the Far East knowledge to Europe and Africa defined much of the humanity progression.

Communication was the magic of science. In the past, Japanese islands tended not to exchange knowledge between each other, not mentioning the historical miscommunication between Japan and China, or Northern Korea and Japan, or between the Philippines from one side, and Malaysia from the other side or even between Russia and all its neighboring countries.

A scientific globalism differs from the political globalism. It has the super wings from one side and the international intellectual piracy from the other side.

With the advance of the global public communication via internet, western medicine found itself in an open access to new medical civilizations. These civilizations were previously concealed for centuries.

The acupuncture from the eastern Asian medicine began to be to be taught in anesthesiology. Different physiotherapy faculties are teaching since a couple of decades ago, the importance of cupping, Tu-ina, and Shiatsu. Many new methods were adopted in speech therapy. Chiropractice, and Osteopathy fields, nutrition and botanics, became full of new knowledge. Ayurveda medicine showed to have many active therapeutic substances and now India is number one country in pharmaceutical production with no doubt. Any launched novel in Tokyo can reach Buenos Aires in 3 seconds and vise-versa.


The Medical Philosophy - A Flashback About the Philosophy of Medicine in History

The profession of being a healer may be one of the first methodical occupations throughout the ages. It took really long time to become a well-defined vocation and pass through different conditions all over the world. It was a basic necessity for all civilizations and a pillar of culture advance.

Thus, in the Eastern philosophy, Confucius in the 6th and 5th century BC, said that self-discipline is the foundation of all achievements.

During the 5th and 4th century BC, medical healers met for the first time a rule of limitation: "As to diseases, make a habit of two things: to help, or at least, to do no harm" Hippocrates 460 - 370 BC. Maybe it was the transforming cutting-edge phrase which led to the formation of the occupation of doctor. A doctor become responsible and not only disciplined.

Between year 200 and 175 BC, in his "work of ethical teachings" and mainly in chapter 38, Ecclesiasticus who was also known as Sirakh of Jerusalem, comprised the following phrases appreciating the profession of physicians:

1. Honor doctors for their services, since indeed the Lord created them. (Source II: Give doctors the honor they deserve, for the Lord gave them their work to do)

2. Healing comes from the Most High, and the king will reward them. (Source II: Their skill came from the Most High, and kings reward them for it).

3. The skill of doctors will make them eminent, and they will be admired in the presence of the great. (Source II: Their knowledge gives them a position of importance, and powerful people hold them in high regard).

4. And he endowed human beings with skill so that he would be glorified through his marvelous deeds.

5. With those medicines, the doctor cures and takes away pain.

Superiority of the profession of medicine did not come from the fact of knowledgeability;
it probably came from the fact of willpower to save human life. In the past, it could be anything beginning with a simple insect bite or a spontaneous delivery that could end up catastrophically at these old times.

The distinctive determination of primitive healers necessitated not only the knowledge, but also the braveness and the discipline of act.

The Medical Philosophy - Prime Definitions of Life, Health and Diseases

It is mandatory to cross a topic like this, before stepping into the gate of immortality since the debate seems to be unresolved regarding the definitions of health and disease from one side and the definition of life on the other side.

Interestingly in the latest centuries, many aspects of medicine started to emerge. Voltaire seriously wrote in the 17th century: "The art of medicine consists of amusing the patient while nature cures the disease." Ironically these words can be applied on some medical conditions, but of course, not on many. Now we think more, we analyze more, and we request information more.

"Be skeptical, ask questions, and demand proof, demand evidence. Don't take anything for granted". Michael Specter says. He continued, "But here's the thing: When you get proof, you need to accept the proof. And we're not that good at doing that."

Dean Ornish said, "I don't understand why asking people to eat a well-balanced vegetarian diet is considered drastic, while it is medically conservative to cut people open and put them on cholesterol lowering drugs for the rest of their lives."

Robertson Davies, a writer without medical background, reckoned that 'the profession of medicine seems to be moving toward a condition where it is principally involved with science'. …so doctors had lost their status as magicians or gods.

Tending to complete this deliberation with the technological advances, we can deduce that the philosophy of medical technology is increasingly defined not just by the character of its human interactions or professional expertise, but also by the type of its instruments, from stethoscope to high-tech imaging machines, synthetic drugs, and prosthetic parts.

While we are evolving, we continuously require a definitive management plan to keep up with all the evaluative current. This was not earlier than 1981, Edmund Pellegrino and David Thomasma, in "A Philosophical Basis of Medical Practice", who suggested that the crisis of modern medicine lies in the lack of a suitable philosophy of medical practice.


The Medical Philosophy - Physicians Remembering Their Initial Objective

There is always a different story, but it always starts with the love to help. Becoming a medical doctor can be a rewarding career choice even though a physician previously knows since before walking into the field, that he will never have the power of a cleric or the authority of an officer or the wealth of a dealer or become famous like an actor.

Love to help fuels a 16-year-old student’s heart till the age of 19, when upon admission to the first year of medicine, he makes all the family’s hearts beat faster.

Growing up in a hospital building during the civil war, I was a physician’s grandson. At the north of the country my grandfather maybe was the earliest surgeon, but surely the most popular. I felt the smiling mercy in his examining hands, and before procedures, I heard the faith in his whispers. At age of adolescence, I was able to detect his discreet tears which were always there when a poor father brought a basket of fruits or some eggs from his home organic farm.
My grandfather did his best to give me this profession, this immense treasure. He gladly watched me rambling at the ward, captivated by his gestures, by his reassuring voice and his different weird armaments… I accepted the challenge because yes, I wanted to improve the world, to fight against all diseases at once, and alleviate suffering of all human beings.

Dr. Nirmal Joshi wrote in his article: Being a doctor was once a job with great purpose. Now it's just a business (The Guardian, February 2014), about his father who was a doctor: "The power of the respect and gratitude that he received was the driving motivational force for a long and rewarding career in medicine. No amount of financial remuneration would have trumped this kind of professional satisfaction."


The Medical Philosophy - Nurtured by Only Love, Is That So Simple?

Of course, it is not. On July 21, 2011 Dr. Danielle Ofri wrote in the New York Times: "I can’t deny that the thought of giving up clinical practice has crossed my mind. Life would be so much easier…."

The amount of spent white nights, the stress of exams, the undigested unfavorable courses, and the suffering of patients convert life of the majority of medical specialists from a wonder world to a vast jail. The life of a physician quickly becomes lifeless, where there is not "light", not enough hope, and not enough rewards.

Here the next step follows, and the population of physicians divides mostly into five figures:

1. The Escapees: those physicians slowly or abruptly transmute fully or partially into administrators.

2. The Revengers: deceived physicians direct a business overlooking the Hippocrates Oath and the main purpose of medicine.

3. The Researchers: those unsatisfied by the shocking truth of practice continue "looking for Utopia".

4. The Masochists: those who stay "there" enjoying the activity of being tortured

5. The Geniuses: living Confucius: "Choose a job you love, and you will never have to work a day in your life."

Well, the most group of individuals to be worried from is group 2 based on their bad reflection on the “social hygiene”. These physicians are the ones who provoke the retardation of innovative medicine and unscientifically attack their business shakers.

At the time of rough criticism, based on own observations, “The Geniuses” and “The Researchers” are real minority in our days; they are those who continue incarnating the ambition of their 16-year-old heart.


Stem Cell History

Stem cells arena may be the most promising area of international medical research today. Stem cells have a fascinating past that has been infected with ambiguities and debates. I will limit the history review to those earliest names in the field.

In 1868, the German Scientist Ernst Haeckel published his model named "Stammzelle" describing stem cell function.

In 1885, the German Dr. August Weismann discussed Stem Cells using the term "Germ Plasm".

In 1905, Dr. Artur Pappenheim, also a German, produced a powerful diagram about stem cell function and differentiation.

In 1908, Russian Dr. Alexander Maximov, included the phrase stem cells as part of his model of hematopoiesis.

Thus, more than 100 years ago scientists presented evidence that stem cells existed, were germinal in nature, and were undifferentiated.
In 1963, Dr. James Till and Dr. Ernst McCulloch, known as the Canadian duo, published more descriptions about stem cells and in the same year, in collaboration with the Canadian molecular biologist and the pioneer in human genetics Lou Siminovitch, obtained evidence that bone marrow cells were capable of what is called self-renewal, a principal feature of the functional definition of stem cells.
1968 was the year when the first bone marrow transplant was performed to successfully treat two siblings with Severe combined immunodeficiency (SCID, which is also known as alymphocytosis, Glanzmann–Riniker syndrome, severe mixed immunodeficiency syndrome, and thymicalymphoplasia).

Rapidly after this latest therapeutic revolution regarding the previously hopeless SCID, and from behind-the-curtain, the interest in stem cells increased so a series of discoveries followed:

1978, stem cells were discovered in human cord blood

1981, first in vitro stem cell line developed from mice

1988, embryonic stem cell lines created from a hamster

1995, first embryonic stem cell line derived from a primate

1997, cloned lamb from lamb stem cells

1998, first embryonic stem cell lines from a human

Today stem cells laboratories are in more than 70 countries. We have in our disposal hundreds of precursor cell types and tissue culture media. Stem cells did not only transfigure the treatment of cancer, they also founded for regenerative medicine, and fueled the emergence of a biomedical industry all over the world.

Stem cell field is a field with health care revolutionizing potential and expectations exceeding all present predictions.

Stem Cells Potency and Potentiality

Zygote, morula, blastula, gastrula, somites, and then organs of a full human body; these are the embryonic phases leading to the formation of a mammalian organism. As Huang, G., Ye,S., Zhou, X. et al (2015) states, following the blastomere formation, at the blastocyst level, embryonic stem cells from the trophectoderm differentiate into two primitive line directions: the neuroectoderm from one side and the mesoderm/endoderm from the other side.

In the review of Medical Embryology book by Ben Pansky, during the embryonic life, at the end of gastrulation, 3 germ lines appear in place.
"Stem cells are undifferentiated blank cells which can differentiate into other types of cells", practically a mantra we hear in the majority of introductions of stem cell articles, but does anyone raise up the next question; how these blank cells differentiate?

Because this subject is rarely raised, it does not mean it is not important; it is just a blind end question currently without complete answer. Almost all living tissues can provide us with stem cells. The difference between one type and the other is the potency. We can discuss 6 types of potency along with their examples:
Stem cells are able to differentiate into other specialized cells and this ability is diverse.

The Totipotency:

The Morula’s cells potency is so high. Cells cultured from the morula can form all body parts and also the placenta.

The Pluripotency:

Blastocyt’s cells have this potency and become a full mammalian body

The Multipotency:

This kind of potency is found in the bone marrow cells, which can be mesenchymal and differentiate into adipocytes, osteoblasts, chondrocytes, myofibroblasts, tenocytes, neural cells, cardiac myocytes, renal tubular cells, skeletal myocytes, endothelial cells, hepatic cells, as mentioned in the article Adult bone-marrow stem cells and their potential in medicine (2010), and the hematopoietic cells which can differentiate into types of blood cell like lymphocytes, monocytes, neutrophils.

The Oligopotency:

Progenitor cells into the organism become many types of tissue (ex: vascular stem cellsdifferentiate into endothelial or smooth muscle cells)

The Bipotency:

Progenitor cells into the organ becoming 1 of 2 types of cells of that organ (ex: Hepatoblasts differentiate into hepatocytes or cholangiocytes)

The Unipotency:

Precursor cells into the tissue becoming an advanced functional type of cells.

How Many Types of Stem Cell Types Do We Know Now?

The absolute number of stem cells is unknown. In a subjective opinion, I think the number of types increase till the ageing process starts. So, the exact age cannot be defined, but practically speaking, it can be estimated at the end of the anabolic phase, starting in each organ independently. Moreover the type of the stem cell (I also call them "the maintenance team") maybe changing, but I will not explain my theory in this dissertation.

Today in 2017, we are 9 years after "the stem cells revolution". The debate is subsiding. Many of the young "first surfers" are becoming more wise and experienced. From the other side, many of the inexperienced opponents disappeared or became just un-influential.

"I think we have to deal with a huge bulk of distorted knowledge, to clean up the stem cells field and rebuild the temple they deserve". In an internet release signed by the author "Kristine" and named Pathology Student, the author wrote at the introduction: Why I created Pathology Student. I love to teach. And write. It’s kind of weird to go through med school and a pathology residency and end up "just" teaching. People think it’s a little weird, but I don’t really care, because I love my job just the way it is.

In the General pathology, Hematopathology(Multipotentvs. pluripotent stem cells. Jul 8,2013), where student ask many questions in the public internet blog, we can find the following information: "Multipotent stem cells cannot give rise to any old cell in the body - they are restricted to a limited range of cell types. For example, there are multipotent stem cells in the bone marrow that can give rise to red cells, white cells, and platelets. They can’t give rise to hepatocytes, or any other cell type, though - so they are not totipotent or pluripotent."

One of the rare works dedicated to the biomolecular basis of stem cell differentiation is "Molecular basis of embryonic stem cell self-renewal: from signaling pathways to pluripotency network". On the 23rd of November 2015, Iain R. Murray and Bruno Péault, Published online Q&A: Mesenchymal stem cells — where do they come from and is it important?
This work defines in an accurate way this type of stem cells and finally uncovers many of their features. Novice researchers in the field of stem cells therapy may undergo a short passage of nomenclature. Thus, a clear-cut differentiation is basic to go into this field.
The EU regulatory classification of cell-based therapies discriminates between minimally manipulated cells for homologous use (transplants or transfusions) and those regulated as medicines which are required to demonstrate quality, safety and efficacy standards to obtain a marketing authorization before becoming commercially available (referred to as Advanced Therapy Medicinal Products; ATMPs) which are further subdivided into somatic cell, gene therapy and tissue engineered products, according to Cell-based therapy technology classifications and translational challenges (2015).


Classification of Stem Cell Technologies

Somatic cell technologies

This technology uses cells from the human body that are purified, propagated, and/or differentiated to a specific cell product that subsequently is administered to a patient for a specific therapeutic treatment.

Cell immortalization technologies

Immortalization technologies have been around some time but are currently not well adopted in the cell-therapy field. The most well-known example of this technology area is the neural stem cell line CTX, mentioned in BMC Neurosci in 2009.

Ex vivo gene modification of cells using viral vector technologies

It is based on gene modifications and still under research.

In vivo gene modification of cells using viral vector technologies

Consist on direct introduction of genetic material into the human body. Although several delivery methods are under development, the most widely used delivery system is to use modified viruses carrying targeting viral vectors that are introduced into human cells via infection in vivo. Still under research, potential indications are numerous and include cancer gene therapy, neurological disorders, monogenetic disorders, infectious diseases, and cardiovascular abnormalities, as stated in State-of-the-art gene-based therapies: the road ahead.

Genome editing technologies

Targeted gene editing may still be considered as an evolving and early stage methodology from a translational viewpoint, but it has the potential to become a disruptive technology within the next decade in the cell-therapy field.

Cell plasticity technologies

This technology holds great promise and clearly has a disruptive clinical potential primarily because of the high probability of an almost unlimited supply of cells and also for the possibility to partly immune match the resulting cell product with the recipient patient, as recalled in Toward the development of a global induced pluripotent stem cell library.

3D technologies

Combining somatic cell technologies or the varieties of cell-therapy technologies described above, with various types of biocompatible materials to solve structural challenges that are often surgical or immunological in nature. I refer my subject review to 3 pioneering works in this futuristic field: Synthetic organs for regenerative medicine. Pedersen et al. 2012, 3D bio-printing of tissues and organs. Murphy et al. 2014, The current state of scaffolds for musculoskeletal regenerative applications. Smith et al. 2015

Combinations of the above

It is a potentially ground-breaking technology like self-formation of complex organ buds into organ-like structures, i.e. organoids, is one example of an emerging technology that could become disruptive.
Sasai wrote in 2013 an amazing manuscript: “Next-generation regenerative medicine: organogenesis from stem cells in 3D culture”.

Cellular products therapy

Another field of interest using cells products and stem cells products like peptides and proteins, fresh extract or lyophilized powder.

The stem cell transplant

One of the most studied and popular fields are the Somatic Cell Therapies, based on the administration of somatic cells named transplant or translocation or relocation.

Two types of stem transplant are delineated:

1- The Autologous Cells Transplant

2- The Allogeneic Cells Transplant

In each type, the sourced stem cells are either embryonic or adult:

Embryonic stem cells

Extracted from womb products; embryo, fetus, placenta, or umbilical cord

Adult stem cells

They are extracted from patients even starting at day 1 of age. Because many ethical and deontological issues are around the use of embryonic stem cells, I will focus in Regentime about the adult stem cells.


What are the most popular localizations of adult stem cells?
While the embryonic stem cells source is the umbilical cord blood, the most popular sources of adult stem cells are:

• The bone marrow

• The adipose tissue

• The peripheral blood

Other sources like the dental root canal are less used in the studies.


Which cells are more superior?

The answer to this question is not so simple, but autologous stem cells were shown to be safe because of the full HLA and surface antigens compatibility so no possible rejection or negative reaction, as well no risk of genetic/DNA contamination.

In 2015, 83,000 clinical trials were registered worldwide. Some of these studies were using the allogeneic stem cells and others the autologous. There is no doubt that the use of embryonic stem cells leads to an ethical clash which is related to the sacrifice of the fetus or embryo. Except to this fact is when the source of embryonic stem cells is the umbilical cord blood or the placenta.

But in my modest personal opinion, the dilemma remains in the embryonic allogeneic cells, where a transfer of foreign genes from the donor to the hosting body stands as an additional risk.

In case the embryonic stem cells are from the same donor, there is no risk of genetic material contamination. As a practical example of this therapy, the use of the umbilical cord tissue derived embryonic stem cells to treat cerebral palsy injury caused by perinatal lack of oxygen.


From inside the bone marrow

There is no doubt that all regenerative medicine pioneers were in some grade inspired by the bone marrow transplant works. The field of Hematopoietic stem cells passed through a long and difficult way until it became after 30 years a well-formed arena. Together with the chemotherapy, they changed the destiny of many millions of blood disorder patients all over the world.

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As we prove that the bone marrow is in fact the mother place of many types of primitive stem cells in Bone Marrow – Home of Versatile Stem Cells, it was chosen by many stem cell therapy pioneers (and I am proud to be one of them), to be outsourcing their studies.
Regarding my own work in this field, I started to publish studies once I was sure all the stem cells are adult autologous bone marrow derived.

2007 was the year when Raphael Rubin and David S. Strayer clearly mentioned in Rubin's Pathology: Clinicopathologic Foundations of Medicine. (Lippincott Williams & Wilkins), that the bone marrow stroma contains mesenchymal stem cells (MSCs). Only one year later, in their article dated 2008, Mariusz Ratajczak et al. wrote “Evidence accumulated that bone marrow in addition to hematopoietic stem cells also contains a heterogeneous population of non-hematopoietic stem cells. Several types of non-hematopoietic stem/primitive cells have been variously described in the literature as: (table 4).

1. Endothelial progenitor cells (EPC)

2. Mesenchymal stem cells (MSC)

3. Multipotent adult progenitor cells (MAPC)

4. Marrow-isolated adult multilineage inducible cells (MIAMI)

5. Multipotent adult stem cells (MACS)

6. Very small embryonic-like (VSEL) stem cells

The Australian Centre for Blood Diseases at Monash University, uncovered 2 years ago in January 2015 some additional amazing facts about the bone marrow, in its publication named The Red Cell Membrane: structure and pathologies, authors said that the blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow. Only mature blood cells contain the membrane proteins, such as aquaporin and glycophorin that are required to attach to and pass the blood vessel endothelium.

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Table 4: Adopted from: Bone Marrow – Home of Versatile Stem Cells. Mariusz Ratajczak, Ewa Zuba-Surma, WojtekWojakowski, Janina Ratajczak, and Magda Kucia. Transfus Med Hemother. 2008 Jun; 35(3): 248–259


The super characteristics of stem cells

A stem cell also has another super feature; it can self-renew, exactly in a division manner, in another term, and does not die! Biological immortality and sometimes referred to bio-indefinite mortality, is a state in which the rate of mortality from senescence is stable or slowly decreasing. Biological immortality is an idea referred to as the late-life mortality plateau.
This was first mentioned in history by Alexis Carrel who was born in 28 June 1873, at Rhône, France. Carrel was interested in the phenomenon of senescence and aging. He claimed that all cells continued to grow indefinitely and did an experiment culturing an embryonic chicken heart for 20 years.

Carrel's experiment by some was never successfully replicated, and in the 1960s Leonard Hayflick proposed that differentiated cells can undergo only a limited number of divisions before dying. This is known as the Hayflick limit, and is now a pillar of biology.

However, L. Franks and others (Loo et al. 1987; Nooden and Tompson 1995; Frolkis 1988) have shown that the number of cell divisions can be considerably greater than that stipulated by the "Hayflick Limit", having practically no limit at all. This was also mentioned by Fossel, et al at the. Oxford University Press. p. 504

The Hayflick limit or Hayflick phenomenon (by Hayflick L. in 2 studies, 1961 and 1965) is the number of times a normal human cell population will divide until cell division stops. Empirical evidence shows that the telomeres associated with each cell's DNA will become slightly shorter with each new cell division until they shorten to a critical length.

In Russia, in the year 2012, and then in the United States and the Netherlands, pro-immortality transhumanist political parties were launched, advertising for immortalism and immortality as a movement. They aim to provide political support to anti-aging and radical life extension research and technologies and want to ensure the fastest possible—and at the same
time, the least disruptive—societal transition to radical life extension, life without aging. Their objective is to make it possible to provide access to such technologies to the majority of people alive today.

A biologically immortal living being can still die from means other than senescence. For instance, it can be through injury or disease.
To close well this chapter, it still needs to define transdifferentiation. In classic embryology, the totipotent stem cell becomes unipotent through successive phases of fate restriction. The steps in this process were thought to be irreversible.

However, recently it was shown in vitro that the fate of multipotent cells can be changed to another germ layer, this is called the transdifferentiation, and this feature has its uses in the world of stem cell research.

The Mesenchymals

Based on the work of Le Blanc et al., mesenchymal stem cells did not show alloreactivity lymphocyte responses due to immune modulations. The group of researchers investigated in 2003 the immunologic properties of Mesenchymal stem cells after differentiation along three lineages: bone, cartilage, and adipose tissues. After growth of cells in medium for 6 or 12 days, the expression of HLA class I increased, but no class II was detected on the cell surface.

Le Blanc et al. (2003) ended up concluding that using MSC grown in osteogenic, chondrogenic, or adipogenic medium as stimulator cells, no lymphocyte alloreactivity was seen, supporting the model that MSC can be transplantable between HLA-incompatible individuals.
Later, mesenchymal stem cells/marrow stromal cells have been extensively tested and proven to be effective in preclinical studies for many disorders.

Upon transplantation into the brain, mesenchymal stem cells promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons, and regulate inflammation, primarily through paracrine actions. They have also been demonstrated by Joyce N. et al in 2010, to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons.
Previously in a step to evaluate the feasibility, safety, and immunological effects of intrathecal and intravenous administration of autologous adult bone marrow derived 40-60 days cultured mesenchymal stem cells, an experiment was done on 15 patients with multiple sclerosis and 6 patients with amyotrophic lateral sclerosis.

Karussis et al. registered transient fever and headache with no major adverse effects. The mean ALSFRS score remained stable during the first 6 months, whereas the mean EDSS score improved from 6.7 to 5.9.

Magnetic resonance imaging visualized the mesenchymal stem cells (MSCs) in the occipital horns of the ventricles indicated the possible migration of Ferumoxides-labeled cells in the meninges, subarachnoid space, and spinal cord (labeling by the superparamagnetic iron oxide ferumoxides (Feridex). Immunological analysis revealed an increase in the proportion of CD4+ CD25+ regulatory T cells, a decrease in the proliferative responses of lymphocytes, and the expression of CD40+, CD83+, CD86+, and HLA-DR on myeloid dendritic cells at 24 hours after mesenchymal stem cells transplantation.

Gao et al. concluded lately in their 2016 work that mesenchymal stem cells are excellent candidates for therapeutic use and that they can potentially revolutionize the pharmaceutical field. They pushed for an improved cell sourcing, to a better understanding of immune mechanisms of MSCs. The authors encouraged as well for an implementation in cell culture protocols for proliferation and differentiation. They also mentioned the cryopreservation and the quality control.

Considering the future, the same group of researchers optimistically spoke about the preconditioned and genetically modified mesenchymal stem cells which may pave the way for the development of numerous treatments for immune disorders.

Because of the complexity in multiple sclerosis disease, the incompetence of a large number of promised treatments urges the scientific society to look for more effective therapies which aims to solve both the immune aggression and its ensuing damage.

Meamaret al. (2016) appraised the potential of the hematopoietic, mesenchymal, and neural stem cells in regards to the self-tolerance restoration, immunomodulation, neuroprotection, and neuroregeneration.

Stem cells in the brain stroke

In the 2017 article Update on cell therapy for stroke, Kenmui rand Wechsler recalled that ischemic stroke is a leading cause of death and disability, and that the current treatment is aiming to minimize the damage through thrombolytics and thrombectomies; however, there are no treatments for reversing the neurological damage once a stroke is completed.

They continued that after reviewing preclinical studies and several recent clinical trials, it was found that cell therapy may be safe and effective method to improve the function after ischemic strokes. Reported safety and efficacy, it may provide a promising new treatment for stroke mainly reducing the disability.

In their publication Update on cell therapy for stroke, Kenmuir, et al. stressed as well on the needed further investigation to define the stem cell therapy methods and indications regarding the size of the infarct, the time, its location, and all other parameters optimizing the result of this therapy.

Reviewing 28 trials between year 1995 and 2016, Detante et al. concluded that cell therapy for strokes had a positive effect on the outcome, and the result suggests that this therapy is beneficial and is expected to help in the designing of stem cells controlled clinical trials (CCT) in large stroke populations.

Stem cells as vectors for neurooncology

Maybe we can put mesenchymal stem cells in a rhetorical image of a “horse”, starting nowadays the most ultramodern type of therapy.

In 2016, a new type of experiment by Kazimirsky and his colleagues was done in vitro on glioma cells and glioma stem cells. These cells were attacked by infected with Newcastle disease virus mesenchymal stem cells (delivery vehicles). The stem cells were umbilical cord derived. The selective attack is believed to be pushed by active homing phenomenon towards glial cells.

The contact of infected mesenchymal stem cells with the tumor cells induced the apoptosis of the glial cell via a mediator named TRAIL. Moreover an inhibition of the self-renewal potential was registered in the glial cells and they became highly sensitive to γ-radiation.

Tissue Engineering and Biomaterials for Neurodegenerative Diseases

Verdes et al. (2017) introduced the basic of regenerative medicine as the use of stem cells, scaffolds, and growth factors, describing a potential for restoring damaged tissues of the central nervous system.

In their study done in the year 2017, they investigated the use of human amniotic mesenchymal stem cells, human amniotic epithelial stem cells (hAESC), and human Wharton's jelly mesenchymal stem cells derived from human umbilical cord being the source, and the potential of the human amniotic membrane as a scaffold and/or source of growth factors to promote nerve regeneration.

The morphological differentiation of these stem cells into neural-like cells was evident after 4-5 days when they acquired an elongated and multipolar shape, and at 21 days when they expressed neural and glial markers. It can be concluded that both human amniotic mesenchymal stem cells and umbilical cord are biomaterials that serve with great potential for use in regenerative medicine for the treatment of neurodegenerative diseases.

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