Stem cells are an enigma. The origin is not conventionally English. As commonly happens with other discoveries, a peculiar phenomenon was observed in nature with some aquatic salamanders and small lizards. These creatures could regrow limb parts they shed when attacked or cornered to save themselves. The Mexican Axolotl could even regrow a part of its former self in full and in such a manner not to be discernible as a new growth. This made scientific researchers think about cells present inside the body which during the process of organogenesis had multiple potential roles and differentiated into specific varieties as need be. This specific differentiation of a multi-potent cell allowed us to have a skin cover over a bony skeleton with muscles attached, and the coordination of neural tissue for volitional and involitional movements and higher function. The form and structure were also determined to some extent, most of them being pre-determined by a genetic coding of DNA in cells.
Life is a mysterious abstract force that is felt or seen, but can never be explained. Nobody knows to date where life is. One thing is certain a complete cell, with the intracellular elements bounded by a membrane or wall, is necessary for the initiation and continuation of life. Interactivity and dynamism define life and the knowledge so far states that local environment and co-habitation determine the final form. At the inception, it was hypothesized that there was a totipotent primordial cell that had, with divisive multiplication and disorganization, the ability to transform into separate lines and create organ systems capable of independent function provided adequate nutrition was supplied. Such a totipotent primordial cell began developmental organogenesis and was found in embryos only. Fertilization of an egg with sperm was required to produce an embryo. The first cell on division equally divided the chromosomes with the genetic code. Further multiplication occurs in a short time before differentiation into the species-specific cell lines occurs. Earnest Haeckel, in 1868, used the term "Stammzellen", a stem cell in English, to name this first pluripotent precursor of all cells. Haeckel was quite old at this stage and was involved in propagating Darwin's Evolutionary theory among the German populace. His 'stem cell' hypothesis was a logical conclusion and the name stuck. Years after, i.e., in the '90s of the same century, while studying the fresh-water flea cyclops, Ferdinand Carl Valentin Hacker, another German, noticed a cell somewhat different in the multicellular milieu. This cell divided into two equal cells and one division went on to evolve into the required organelles and covering cells, while the other cell maintained the continuous repetitive division so that it will develop into a specific tissue type if needed. Hacker's observation corroborated Haeckel's proposal and he used the term Stammzellen - stem cell - for the repetitive dividing germ cell line. The name "stem cell" was formally given by Edward Wilson in 1896. This was a conflicting period with Darwin's theory of natural selection and survival of the fittest on one side, and Lamark's proposition of hereditary transmission of characters with the change of some of the properties with time and transmitted as such. Moreover, there was a paradox regarding the ultimate fate of this renewable stem cell line - if there was unit-by-unit repair and replacement of the old structure then a question of perpetuity arose that was improbable at that time.
So stem cells had principally the following properties that defined them --
1. Self-renewal, i.e., the capability of proliferation and growth by
simple undifferentiated cell division.
2. Potency for differentiation to specialized cell types.
Asymmetric cell division is necessary in the multi-potent cells whereby one line of division produces the unadulterated self-renewal cells, while the other line of cells, after division, show some intracellular changes pointing towards the final tissue it is destined to replace or heal. This differentiation can be analyzed but cannot be predicted - a stochastic potency.
Initially, stem cell research was done with animal embryos (Mouse cell embryos were the most common). The finding of stem cells clumped at the inner layer of the blastocysts and having pluripotent properties, made investigators upgrade usage to aborted human embryos. However, as always, religion and enthusiastic activism lead to a holding back of such activities. A later partial revoke of the religious ban, modern techniques of single-cell biopsies and transfer of nuclear material with the genetic code into other viable cells, and Yamanaka's method of conversion of mature adult fibroblasts into multi-potent stem cells changed the attitude of the basic researchers.
The attitude and knowledge about stem cells at this time were restricted to the cells constituting the embryo and thus were called embryonic stem cells. However, though these are one of the earliest in cell lineage, these are distinct from the progenitor cells (which cannot divide indefinitely) and the precursor/blast cells (which can only differentiate to blast cells after fertilization). In the mammalian world, the first indication of stem cells is along the inner face of the developing embryonic blastocyst. Further development converts these pluripotent cells into the three germ layers -- the ectoderm, the mesoderm, and the entoderm. Finally as directed by the genetic code transferred during fertilization, the destined form resembling the original species is created. A collection of stem cells on the inner layer of the blastocyst is found at this stage. The scheme as follows simplifies the hierarchy and lineage of the stem cells: -
EGG + SPERM --> FERTILIZATION --> EMBRYO --> ZYGOTES (simple division up to 8 cells) --> PROGENITOR/TOTIPOTENT /OMNIPOTENT CELLS (capable of creating both embryonic and extra-embryonic cells like the amnion, umbilical cord and placenta)--> MULTICELLULAR MORULA --> BLASTOCYST (buries and anchors to the uterine endometrium) --> STEM CELLS (first clump of stem cells in the inner layer) --> Development & evolution into MULTI-POTENT CELLS (may develop several related systems during differentiation) --> OLIGO-POTENT (capable of differentiation into lymphoid & myeloid tissue) & UNI-POTENT CELLS (can differentiate into a single system of cells only).
From conception and the 2nd to the 8th week the embryo's name is retained. Thereafter, the evolving being is called the fetus till birth. It is important to remember that these are the Embryonic stem cells (ESC) and interested bio-scientists in the early days.
Availability of stem cells for research to date could be --
1. Amniotic fluid.
2. Embryo.
3. Fetal.
4. Infants & babies.
5. Adult or somatic, and lastly the new development of
6. Induced fibroblast adult/ mature stem cells or induced pluripotent stem cells (iPSC).
Differentiation and maturation to adult or somatic stem cells and further directional development to targeted cell type is the goal. Though the results are not as expected to date and after intensive research, scientific researchers strive to find a solution to the management of untreatable conditions which are progressive as stem cells were discovered towards the end of the last century.
Studies into stem cells were slow and a few carried out serious research in stem cells, interest in the matter was at its lowest till the successful cure of a leukemia patient exposed to a dangerous dose of radiation in a nuclear plant in Yugoslavia. In 1958 Georges Mathe, a French oncologist experimentally did a haematopoetic transfer of cells from the bone marrow in a matched patient and found that the diseased cell of the patient is replaced by a new generation of healthy blood cells and the bone marrow were producing altogether new batches of healthy cells thereafter. 1960 saw Ernest Maculloch and James Till, from Toronto, and Andrew Becker, of Ontario Cancer Institute, devoted their efforts and were able to unfold some of the mysteries of stem cells. Only therapeutic ventures into limited organs and conditions were possible and mutagenic effects on the haemopoietic system and some neural diseases could be reversed by the start of the millennium. Religion again interfered and a restriction was enforced on the use of embryonic or similar stem cells for research. 2006 saw the Nobel prize awarded to Shinya Ramayana for the discovery of a method by which adult fibroblasts could be converted back into pluripotent stem cells. These are the so-called induced pluripotent stem cells or iPSCs. This rejuvenated the stem cell scene at that period and rekindled fresh hope for treating certain irreversible morbid diseases. The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.
Stem cell therapy offered certain advantages: --
1. The most advertised aspect is avoidance of the morbidity and
pain associated with surgery. Renewal of dead tissue with
the rejuvenation of activity aspires. There is a definite
reduction in scar size.
2. Stem cell therapy uses the patient's cells cultured before
increasing the number. Immunity-related issues do not happen.
3. Adult, multi-potent, and mesenchymal or somatic stem cells are
most used for intractable conditions where the result is still
uncertain and a slight symptomatic improvement reap hugely
psychological score. This is usually the feature of chronic pain
associated with osteoarthritis, ligament tear, spinal
degeneration, etc.
4. Definite treatment benefits with haematopoetic diseases,
sickle cell anemia and some leukemia.
5. Parkinson's disease and some other neurodegenerative
illnesses that lead to muscle dystrophy also is claimed to
benefit from stem cell therapy.
6. Beauty clinics and geriatric therapy employ a comprehensive
package with hope. Such treatment at least does away with
repeated intracutaneous botulinum injections to straighten out
wrinkles. This gives hope and at least no harm is done.
The cardiovascular system is one of the main targets of stem cell therapy. Unresponsive angina, irreversible tissue destruction in myocardial infarction, ischemic cardiomyopathy, cardiomyopathy with loss of power, etc., are usually treated thus. It is believed that the renewal of dead tissue in the various forms of cardiomyopathy can revert the condition and regaining the pump power is a matter of time. However, the reduction of the scar does not lead to the conical geometric form. The myocardial whorl, where the contractile muscle sheets are wound around each other, is deranged. The repaired heart becomes globular and earlier power is no longer there. Remodeling of the atherosclerotic vessels also does not occur but neo-endothelialisation of a diseased artery has been claimed. The '90s and the early millennium saw many studies where stem cell therapy has been combined with surgical or laser revascularization in an attempt at an acceleration of myocardial remodeling. The hope was forceful pump action and adequate perfusion. However, the time needed is not acceptable, and even if catheter-guided specific delivery to the desired region of the heart is possible, the final result can be erratic. Increased arrhythmogenicity is another issue.
Vascular research at present consists in seeding with stem cells of cell-free autologous collagen and similar material scaffolds for the reconstruction of cylindrical fluid transporting conduits and competent one-way valves of appropriate sizes with autologous material. The concept and the model are interesting and there seems to be some light at the end of the tunnel.
Hair loss is another area where stem cell therapy is supposed to work through the renewal of follicles. Revival of skin lustre (smoothening of wrinkles that needed repeated intracutaneous injection of a particular dose of botulinum toxin) as a part of beauty treatment and geriatric medicine are added areas of prospect. Numerous stem cell clinics have been created where services to improve chronic diseases as mentioned above. Though results may not be guaranteed, common people attend these clinics with hope.
So far nothing dramatic or our course-changing tent method has been found but stem cell research is continuing in a big way. The destruction of embryos for the procurement of stem cells proved to be very controversial, especially for people with religious beliefs. US President George Bush even had to sign a declaration banning the use of human embryo cells in stem cell research. Obama, his successor, again partially revoked the ban allowing research to continue. By this time, however, Yamanaka had developed the iPCS technology and Yamanaka-inducing agents (Yamanaka factors) like a combination of oct-4, sox-2, c-myc and klf-4 were widely used for converting mature fibroblasts into a pluripotent precursor cell. To this were added Somatic cell nuclear transfer (SCNT), Single-Cell blastomere biopsy, Amniotic fluid stem cells (AFSCs), and Umbilical cord blood (UCB) derived cells. The contributions were from Harvard, Wake University, Advanced Cell Technologies, etc. The single-cell biopsy and transfer of embryonic cell nuclei into somatic cells were path-breakers in stem cell research. Cells from the umbilical cord and amniotic fluid also increased availability and nature of potency (i.e, pluripotent or multi-potent) substantially. Epigenetic and clonal modification is a possibility in embryonic stem cell research. The increased availability of different types of stem cells will increase the probability of controversies. However, for the potential benefits, tissue engineering, and regenerative prospects stem cell therapy remains a prospect for the future.
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