The stem cell supply breakdown theory focuses on aging derived through pathologic problems. Research in the field of stem cell and decline in adult stem cell differentiation is comprehensively expanding day-by-day and still a work-in-progress topic.
Stem Cell Supply Chain
An appropriate way to simplify the introduction to stem cell supply chain would be to categorize the different 210 kinds of cells present in our body into five types.
1. Pluripotent Cells
Human embryonic stem cells (hESCs) as well as induced pluripotent stem cells (iPSCs) are cells that have the potential to differentiate in to various cells and categorized as pluripotent cells.
2. Relatively Undifferentiated Multipotent Somatic Cells
Some examples are Mesenchymal Stem Cells (MSC), pericytes and Hematopoietic stem cells, cells usually present in vascular walls as well as in bone marrow. These categories of multipotent cells have the ability to differentiate into various somatic cells.
3. More Differentiated Stem & Progenitor Cells
Progenitor cells such as myoblasts, endothelial as well as satellite cells in muscle tissue are cells that are able to differentiate into only particular somatic cell types
4. Normal Body Somatic Cells
Normal Body somatic cells includes red blood cells, keratinocytes, leukocytes, melanocytes, cardiomyocytes, langerhans cells.
5. Senescent cells
Senescent cells are cells that have reached a final stage and cannot further undergo cell division.
Some progenitor cells have many other lines of specialization, yet the classification is enough for this explanation. All these cells mentioned except senescent cells have the possibility to differentiate and reproduce into other types of cells
Cells of an individual are of the same genome however, the DNA of each cell is slightly differentiated through epigenomic marks. The variation in the cells can be demarked through the epigenomics in the DNA of the cells. Some examples are “histone acetylation”, binding-site molecular folding and DNA methylation.
All cells excluding category 5, can naturally divide further and thereby liable to, cell damage, mutation and oncogenesis. The first type of cell in category 1 does eventually differentiate and turn into all other types of cells category 2, 3, 4 and 5. For instance, cells in category 2 may have to go through a multitude of lines of cells before turning into category 4 cells.
Human embryos (category 1) in the supply chain process constantly progress through life and during the aging process more of the higher hierarchy of cells will remain, category 4 and 5. The contrary applies to category 1, 2 and 3, which become less prevalent as people age. The aging process can thus be controlled by managing a young (category 1,2 and 3) and health cellular supply chain. An abundance of senescence cells (category 5) is negative to the health of the cellular-chain.
Normal Body Somatic Cells (category 4) is responsible for the body functioning. They try to decrease damage and do also ensure that the intra-cellular environment remains healthy by eliminating proto-cancerous and damaged cells via apoptosis. Category 4 cells are also responsible to assure that category B and C cells does properly evolve to replace the somatic cells (category 4).
Somatic cells must assure that category 2 and 3 cells are healthy enough to differentiate into other types of cells. As mentioned, as people grow older the amount of category 1 cells decrease, leaving fewer cells to create category 2 and 3 cells and according to this theory, this is considered a general cause for aging.
Facts about Stem Cells & Stem cell niches
As research in the field of stem cell is constantly evolving many facts might change in the coming month. The supply chain mechanism of cells transforming from category 1 up to category 5 occurs until the end of the lifespan. Aging is theoretically caused because no more stem cells are available, but if these types of cells (category 1) were injected into the system, the body would revitalize and remain young.
Stage of Development
Some organism reaches a point where no more category 1 cells (human embryos stem cells) are available to differentiate due to depletion. The supply chain in such instances is affected as for example “mesenchymal stem cells” are constantly required to produce new tissues. Furthermore, in case of blood loss, “hematopoietic stem cells are required to produce new blood cells, ‘throughout the life of an organism’. Cells that decease due to trauma or apoptosis must be replaced.
Aging associated with degradation of functional organs, such as hair turning gray is found to be caused by depletion of melanocytes stem-cells (MSCs). Recent “empirical research performed on mice” shows that DNA damage negatively impact on “MSCs in hair follicles”.
The ability of stem cells to differentiate and reproduce depends on the microenvironment as well as the health of stem cell niches. Human embryonic stem cells are given signals to differentiate or proliferate in case of tissue injuries. The proliferation and differentiation of cells (category 1, 2 and 3 cells) decline through aging. The “regenerative capacity of stem cells falls with aging” and hence limits the ability to restore tissues needing repair and maintenance. This tends to cause “epigenomic programming.”
However, stem cells (category 3) can be reactivated. The expression of notch activity can activate satellite cells (cells able to regenerate). Inducement of Notch ligand and Delta post to an injury increases the notch signal and there by becomes more responsive to, for example, injuries. Injecting notch activity re-makes old cells more active and gives back their ability to repair tissues. “Appropriate conditions can thus make old cells more responsive”.
Some Research Findings – Stem Cell –
In a published research, ScienceDaily, September 2009, “Human Induced Pluripotent Stem Cells Retain Some Gene Expression of Donor Cells” gave an additional insight in to stem cells. The research concluded that induced pluripotent stem cells (iPSCs) are alike human embryonic stem cells. However they have a transcriptional signature. There is a degree of memory withheld in cells. The use of neural stem cells, with a single factor can actually re-program a cell into a pluripotent state. This cell can thereafter differentiate in to any other cell required by the body according to Muotri. Previously, a four factor combination was used and now a single factor does the same work.
In the future induced pluripotent stem cells (iPSCs) are going to become more widely used in therapeutic application compared to embryonic stem cells. Pluripotent cells are able to transform into any somatic cells without rejection by the immune system compared to cells taken from somebody else.
Stem cells in relation to their niches as well as environmental messaging correlated to cell differentiation division are constantly being comprehended. Many studies are already in place, a new paradigm is “HSCs (Haematopoietic stem cells) as well as HPCs (Haematopoietic progenitor cells) integration into bone marrow as an activator”. Other research studies focusing on category 2 and 3 cells have been performed. (“study 1” and “Study 2”)
Stem cells through evolution reaches cell senescence, and the lifespan of the cell is according to theory going to be affected by telomerase inducement, which will limit its cell division lifespan. A recent “study in 2008: Replicative Senescence of Mesenchymal Stem Cells: A Continuous and Organized Process” focused on human MSC over time. Mesenchymal stem cells studied in vitro did produce 7 to 12 cultivated routs whereby different markers could be identified such as enlargement, morphological abnormalities, proliferate arrest and attenuated expression. A modification to the general gene expression was seen as a marker for MSC cultivation at various passages. The down-regulation at each passage through proliferation was apparently not caused by telomere shortening according the study.
The differentiation process of stem cell involves various proteins, like “survivin”. It is usually used in cancer therapies as an apoptosis inhibitor. A study illustrates “survivin role in hematopoiesis and the inducement of survivin is also necessary for erythroid differentiation”. This protein is involved in “stem cell proliferation as well as differentiation of pathologies such as cancer”.
Stem Cell Supply Chain Association to Aging
There is a constellation of causes related with the supply chain that can increase the pace of aging. Some hard reasons are:
1. Depletion of healthy adult stem cells
2. The supply chain starts to weaken its pace. (lower rate of differentiation of adult stem cells)
3. Stem cell niches are experiencing some problems
Each of these three causes are explained
1. Depletion of healthy adult stem cells
It is a mere fact that adult stem cells experience, damage, senescence, mutation, oncogenesis, apoptosis amidst other setbacks that can lead to the loss of a cell. The gradual depletion of adult stem cells impairs maintenance, replacement and regenerative capacity, which develop common signs of aging.
Research related to mTOR signaling seems to be associated to multipotent stem cells like HCSs (“Hematopoietic stem cells”). HCSs are stem cells that produce different types of blood cells.
A publication in April 2008, mTORC1 signaling governs hematopoietic stem cell quiescence: “The stringent regulation of hematopoietic stem cell (HSC) quiescence versus cell cycle progression is essential for the preservation of a pool of long-term self-renewing cells and vital for sustaining an adequate supply of all blood lineages throughout life. Cell growth, the process that is mass increase, serves as a trigger for cell cycle progression and is regulated predominantly by mammalian target of rapamycin complex 1 (mTORC1) signaling. Emerging data from various mice models show deletion of several mTORC1 negative regulators, including PTEN, TSC1, PML and Fbxw7 result in similar HSC phenotypes characterized as HSC hyper-proliferation and subsequent exhaustion, and defective repopulating potential”
To be more explicit, when the negative regulator of mTORC1 is having problems, an uncontrolled amount of hematopoietic stem cells are produced. This leads to a depletion of these distinct cells hampering the supply chain of stem cells.
Regulation of negative mTORC1 is thus essential to maintain the stem cell supply chain. Another transcription factor is FOXO. Foxo3a are required to assure that “hematopoietic stem cells remain healthy”. The completely hematopoietic development requires a systematic balance of the process of HSC’s self-renewal and differentiation into effector cells. A proper balance between self-renewal and differentiation sustains hematopiesis during a lifespan. A high differentiation or self-renewal can cause leukemogensis. However, self-renewal and differentiation process is poorly understood until now. It is only known that it plays a vital role in the cell cycle: oxidative stress and apoptosis. “FoxO seems to have role in regulating HSC”.
2. The supply chain starts to weaken its pace. (lower rate of differentiation of adult stem cells)
Aging related to somatic stem cells (SSCs or category 2) is associated to the constant renewal of organs. Somatic stem cells can replicate into normal somatic cells through cell division. SSCs are related to particular tissues, yet they can differentiate into other cell types as well. They can generate progenitor cells (category 3) that can also turn into category 4 cells. An example is skin cells produced from differentiation of epithelial stem cells. In emergency conditions during burns or wounds stress signals will make SSCs generate progenitor cells for replacement. It is a fact that somatic stem cells differentiate through an alteration in gene expression in case of organ damage. The cell process involved in cell signaling is in progressive research now.
Aging is caused by a declining SSC differentiation process leading to a weaker rate of regeneration of organs. The declining speed is related to “shortened telomeres/”, cell senescence, particular protein accumulation in cells and damaged of SSCs. (Fact 1, Fact 2, Fact 3, and Fact 4)
The aging process of SSCs such as hematopoietic stem cells is instigated as progenitor cells are changed into basophil, macrophage or eosinophil. During the differentiation process, the amount of SSC cells remains constant as another one is produced. However, the cells age because of telomere shortening. Shortening of telomeres does in the “longer-run cause cell senescence”. Category 5 cells are thereby produces, which can be abnormal or malignant somatic cells that make elders susceptible to old-age-related diseases.
Recent study, give more evidence of the declining level of adult stem cell differentiation. A report entitled “TAp63 prevents premature aging by promoting adult stem cell maintenance” suggests that in the absence of the p53 family member (TAp63) an individual might experience premature skin aging. Tap63 is necessary to control dermal precursors and epidermal. In vitro study conducted on mice with removed TAp63, experienced early aging and suffered from skin ulceration, blister, senescence of hair follicle dermal and epidermal cells. The maintenance of Tap63 in adult skin stem cells can create genomic stability, which can avoid early aging of tissues.
3. Stem cell niches are experiencing some problems
Considering the microenvironment and close-inter-relationship that exists in stem cell niches, various problems can arise. For instance, a trauma can affect the stem cell population. Therefore, it is essential to comprehend effects of external factors on hESC self-renewal and differentiation. This can enable development of “regenerative medicine”. Niches are expected to assure that stem cells are in quiescence. To give an example, the osteoblastic niche assures proper balance of osteoblastic cells (OBs) and hematopoietic stem cells (HSCs) by passing through a signaling process. The mechanism is geared to safeguard HSCs, and “enable sustainable quiescence hematopoiesis”.
As a theory, the concern is on the breakdown of the supply chain for new somatic cells. The priority is on adult stem cells. Here a close relationship exists with “programmed epigenomic changes theory” and the subsidiary theory on “Epigenomic Changes In Dna Methylation And Histone Acetylation”. These theories are complementary and compatible. It has already been mentioned that differences across cell types (category 1 to 5) is in the epigenome and not the genome. Genes in the body are identical. In other words as category 1 cells differentiate they are marked with different epigenomic histories. This can be because of DNA methylation or histone acetylation.
More study is being done to understand this alteration in epigenomic during different stages of the life cycle of cells. However if a category 4 cell is re-engineered back to category 1 (IPSC cell) its epigenetic signs are erased. It might thus be possible that these three different theories hold a common attribute towards aging.
Research in the field of stem cell supply chain is new. Studies will certainly increase in the field. Exponential knowledge in stem cell supply chain will without doubt be identified.
Reference:
1. Anti- aging firewalls the science and technology of longevity.
Further Reading
1. A Road Map to Anti Aging Theories
Sun, Jan 10, 2010
Anti Aging, Anti Aging Theories, Stem cells