Introduction to Stem Cell Basics

Stem Cell Basics- What are Organ and Tissue Stem Cells

Organ and tissue stem cells are rare cells resident in the body’s organs and tissues that divide continuously to replace constituent cells lost to natural cell death, normal wear and tear, disease, or injury. Stem cells are the only cells in an organ or tissue that have the ability to divide to produce all the different constituent cells that make up their respective organ or tissue. When a tissue stem cell divides into two cells, one of the new cells is another stem cell, whereas the other cell is a committed progenitor that divides further to produce new constituent cells. This remarkable process is called asymmetric self-renewal; and it is an exclusive ability of organ and tissue stem cells. Stem cells can make committed progenitor cells, but committed progenitor cells cannot make stem cells.

Stem Cell Basics- What is the Difference Between Adult, Embryonic, Pluripotent, Induced Pluripotent, or Metakaryotic Stem Cells?

Organ and tissue stem cells are one of two types of true “stem cells.” Because they are found in the organs and tissues of adults, they are often referred to as “adult” stem cells; but they are also found in the organs and tissues of children. More recently, they have been called “distributed stem cells,” because they naturally distribute the constituent cell-type potency of the early embryo. The earliest embryo formed by fertilization is totipotent, meaning that it has the ability to produce every constituent cell type in the mature body. In contrast, tissue stem cells are either uni-potent or multi-potent in a tissue-specific fashion. So, uni-potent adult lens stem cells replenish only one mature cell type that forms the lens of the eye. In contrast, multi-potent small intestinal stem cells replenish several different cells that form the lining of the small intestines. However, neither of these tissue stem cells has the ability to replenish the tissues of each other or any other different organ or tissue. Tissue stem cells have also been identified in birth related tissues like amnion fluid, amnion membranes, the placenta, and the umbilical cord.

Embryonic stem cells (ESCs) are artificially produced from the embryo at the stage when the cells used are no longer totipotent. Because the embryo, which is a living human being, is destroyed by the procedure used to derive human ESCs (hESCs), production and use of these cells remains controversial. When injected into mouse embryos, mouse ESCs (mESCs) show the property of pluripotency, meaning they possess the ability to produce all the cells in the body except those that form the placenta. However, outside of embryos, in cell culture both mESCs and hESCs have been shown to have primarily fetal pluripotency. Though they can be instructed to make many different cell types characteristic of constituent cells at the fetal stage of development, it has proved very challenging to get them to make cells characteristics of the organs and tissues of children and adults.

Induced pluripotent stem cells (iPSCs) have potency properties that are very similar to ESCs. In addition, like ESCs, they do not occur naturally. However, whereas ESCs were made by manipulation of the culture conditions of embryonic cells, the main principle for production of iPSCs is manipulation of the genetic control of mature adult cells. In both cases, the artificial manipulations result in many gene mutations and alterations that compromise the use of the cells for cell therapies. Both form tumors at a high rate.

By the strict definition of “stem cell”, ESCs and iPSCs are not stem cells. They lack the asymmetric self-renewal that defines organ and tissue stem cells. When ESCs and iPSCs are instructed to make constituent cells, they convert to become the next stage of constituent cell production; and their stem properties are lost.

A recently discovered and described second type of stem cells is metakaryotic stem cells. They are found in the developing fetus and divide with asymmetric self-renewal to establish new organs. Curiously, they do not organize their DNA into typical condensed chromosomes for cell division like adult tissue stem cells. Unlike embryonic precursor cells, metakaryotic stem cells can be found in adult tissues, too, though at very low frequencies. Currently, whether a lineage relationship exists between adult tissue stem cells and metakaryotic stem cells is unclear.

Stem Cell Basics- What is a Stem Cell Line?

Operationally, “cell line” refers to a culture of cells produced at one time and then maintained continuously in culture for extended periods of time, on the order of months to years. Characteristically, cell lines can also be stored by freezing at very low temperatures (< 140oC) and then thawed for continued culture. Cell lines are sufficiently robust for growth that samples of them can be transferred to other investigators, like cuttings from a favored plant, for continued growth and additional studies.

Stem Cell Basics- What is a Stem Cell Biomarker?

A biomarker is a specific indicator of the presence of a biological entity, feature, or property, which in this case is a stem cell. Typically, the indicator is some type of observation or measurement. When the indicator is seen or quantified, one concludes that the corresponding biological equivalent is present. Biomarkers are used to detect and quantify the biological factor of interest. Observations and measurements can be made by imaging, chemistry, electronics, and complex integrated procedures.

The ideal biomarker is one with high sensitivity, high specificity, and accordingly high predictive value. Commonly used “stem cell biomarkers” have good sensitivity, but very poor specificity (e.g., CD34, CD133, CD90). The poor specificity is the result of natural tissue biology. In morphology and cellular properties, tissue stem cells are extremely similar to the committed progenitor cells that they produce in much greater numbers. As result, it has been difficult to discover biomarkers that can identify and quantify tissue stem cells specifically without confounding by committed progenitor cells.

New generations of stem cell biomarkers have been described recently that do not rely on the impossible requirement of obtaining highly pure populations of stem cells that are free of committed progenitor cells. The basis for these biomarkers is identification of cells under going asymmetric self-renewal, which is a highly exclusive property of tissue stem cells. In addition, to being expressed by such cells, the new biomarkers show localization patterns inside the cells that are also unique to asymmetric self-renewal.

Stem Cell Basics- How are Stem Cells Used in Medicine?

There are two main approaches for stem cell medicine, homologous and heterologous.

The first, and the approach for which there is by far the most experience, is homologous tissue cell restoration. The quintessential, approved therapy for this approach is blood stem cell transplantation. In this case, either the patient’s own stored stem cells or stem cells from an immunologically matched donor are used to restore diseased or damaged tissue of the same type from which the donor stem cells were harvested. So, many therapies are approved for using blood stem cells – also known has hematopoietic stem cells (HSCs) – to restore mature blood cell production. Donor sources for HSCs include autologous sources stored from the patient or allogeneic sources from donors including bone marrow, umbilical cord blood, and stem cells induced to enter the bloodstream (“mobilized’). There are about 19,000 HSC transplants performed in the U.S. each year, and 68,000 worldwide. Other forms of homologous stem cell transplantation include corneal stem cell transplant, which has realized significant success, and pancreatic islet transplantation, which has not because of insufficient supplies of donor pancreatic stem cells.

Not all types of homologous stem cell medicine employ stem cell transplantation. With the advent of pluripotent cell types, both hESCs and human iPSCs (hiPSCs), investigators have looked for means to exploit the ready supply of prolific pluripotent cells. Insufficient cell supply can be a limitation in homologous adult tissue stem cell transplantation therapies. However, since the tumorigenic properties of pluripotent stem cells preclude their transplantation, their mature differentiated cells are transplanted instead. Current clinical trials of this type include retinal neuronal precursors for blindness and insulin-producing pancreatic beta-cell precursors for type I diabetes. If these studies succeed in meeting the requirements for immune evasion, effective differentiation and function, and tumor avoidance, they will still face the challenge of maintaining tissue renewal without adult tissue stem cells.

The second, and presently major, approach to stem cell transplantation therapy emerged in the last decade as a result of the discovery of adult tissue mesenchymal stem cells (MSCs) derived from bone marrow or fat tissue. The asymmetric self-renewal capability of these “adult” stem cells is unclear. Currently in many clinical trials they are under investigation for their ability to accelerate wound healing and tissue injury repair in tissues from which they were not derived, hence “heterologous.” Though there is little supporting experimental evidence for the concept, MSCs are envisioned to secrete growth factors and other healing factors that promote increased blood flow and other effects that accelerate tissue repair. Treatments of this type are also on-going in general medical practice. This rapidly expanding activity is raising concerns of injury to patients not because of adverse physical effects, but instead because of poor treatment design and lack of a sound scientific basis to justify the treatments.

Stem Cell Basics- What is Regenerative Medicine?

Regenerative medicine is the field of medicine that emphasizes the manipulation of organ and tissue cells’ ability to reproduce themselves to develop better treatments and cures for diseases, disorders, and injuries. Regenerative medicine includes stem cell medicine. Stem cell medicine is the branch of regenerative medicine that focuses on the use of stem cells, their properties, and knowledge about them to develop better treatments and cures for diseases, disorders, and injuries.

Stem Cell Basics- Is Stem Cell Medicine Safe?

In homologous transplants, organ and tissue stem cells, themselves, have proven to be very safe for transplantation. However, depending on the medical indication for stem cell transplantation, the overall treatment can be highly morbid or even fatal. A common risk due to poor immunological matching is graft versus host disease (GVHD), which can be highly traumatic and result in death. In many cases, patients have previously undergone highly toxic therapies for cancer treatment, followed by bone marrow ablation during attempts to eradicate cancer cells before the restorative transplant. In these cases, though the patient may survive the transplant and their cancer, they face a future of chronic organ dysfunction that can end in a need for additional organ transplants (e.g., heart, lung, or liver). In the case of umbilical cord transplants, which have fewer blood stem cells, there is the risk of obtaining too few stem cells, which can result in death if a second transplant donor is not available and effective.

Thus far, few adverse physical effects of have been attributed to heterologous stem cell transplantation treatments, which usual employ autologous cells that eliminate the risk of GVHD. Also, currently, heterologous transplants are mostly performed with patients of otherwise generally healthy constitution. One common feature of the few studies reporting tracking of transplanted mesenchymal stem cell preparations is that the cells are rapidly loss from detection. An important lacking in these clinical trials, as well as in treatments by physicians in their general practice, is knowledge of the quality and number of stem cells being transplanted by the poorly defined cell preparations used. So, the greatest risk in heterologous stem cell transplantation appears to be the possibility of misled hopes when no benefit could occur at all, despite the significant amounts of money paid by patients for the treatments.

Stem Cell Basics- Can Stem Cells Help with Alzheimer’s, Multiple Sclerosis, Autism, and Cancer?

In the case of cancer, blood stem cells play a crucial role in the rescue of cancer patients from high dose therapies designed to eradicate their cancers. However, stem cell transplantation medicine holding improved treatments or cures for the other neurological illnesses seems an unlikely prospect for two reasons. One, the underlying causes of AD, MS, and autism do not appear to be stem cell related; and, two, the possibility that heterologous stem cells might produce factors that could alter the course of these illnesses has little, if indeed any, basis in current scientific knowledge of the nature of these disorders.

There are some who have suggested that investigation of the cell development properties of embryonic stem cells could shed light on the biological mechanisms responsible for these disorders, but so far such insights have not emerged from this approach. Opponents of this suggestion have argued that it will be impossible to learn from studies with embryonic cells about diseases that may initiate in adult tissues.

With a different approach, iPSC cells have shown potential to shed light on adult disease mechanisms and to develop model cell systems for their more detailed investigation. In the case of autism, neurons developed from iPSCs derived from the blood cells of autistic children display dysfunctional properties that are not observed in iPSC-derived neurons from non-autistic children. Similar success has been described for inherited heart disorders. It is possible that the success with autism reflects a unicellular embryonic etiology, like the inherited heart muscle cell disorders, which may not pertain to disorders involving more complex cellular interactions. However, similar investigations in progress for AD and MS could also reveal important insights to key mechanisms responsible for these illnesses as well.

Stem Cell Basics- How are Stem Cells used in Medicine?

Currently, the most widely investigated and employed stem cell technology is the production of induced pluripotent stem cells (iPSCs) and the study of their properties, in particular their ability to produce organ and tissue constituent cells. Many laboratories pursue research towards increasing the efficiency of producing iPSCs and increasing the stability of the cells ability to produce constituent tissue cells. Advancing the production of iPSC-derived cells with fetal properties to cells with properties of mature adult organs and tissues is a highly sought objective.

In research, their continues to be significant effort to address the challenges of translating knowledge of normal organ and tissue stem cells to better clinical utility. Investigators continue to pursue discoveries that will lead to better technologies for isolating, purifying, expanding, cloning (i.e., producing many cells from a single cell), identifying, and counting organ and tissue stem cells. Although none of these capabilities are required for currently approved stem cell therapies like blood stem cell transplantation, such therapies would still benefit from them; and newer therapies with stem cells from other tissues may not be possible without achieving these advances.

In medicine, a highly utilized stem cell technology is characterization of stem cell-containing populations with the biomarker CD34. CD34 is a factor found on the surface of hematopoietic stem cells as well as on stem cells found in several other adult tissues. Though CD34 mainly reports on committed progenitor stem cell number, it is often referred to as a “stem cell biomarker” and employed as such.

Stem Cell Basics- Are Stem Cells Used in Drug Development?

Currently, there is very limited use of organ and tissue stem cells in drug development. This situation exists because tissue stem cells are hard to isolate, purify, clone (i.e., grow a large culture from a single cell), expand in number, identify, or quantify. These challenges pretty well eliminate any chance of producing the types of technologies needed for evaluating the interaction of drugs with tissue stem cells.

There has been a limited use of embryonic stem cells to evaluate effects of drugs and environmental toxins on embryonic development. Such technologies have not really taken off in the pharmaceutical industry largely because their relevance to human embryonic development in the body is unclear. In contrast, induced pluripotent stem cells (iPSCs) initially motivated a rapid intensification in effort to employ them to produce mature cells for tissues like liver, heart, and neurons for drug evaluations. However, this initial enthusiasm has been dampened by the revelation that iPSCs produced constituent cells with mainly fetal properties and not the mature adult properties desired by the pharmaceutical industry.

A few companies have pursued development of a new class of cancer drugs that targets cancer stem cells. Cancer stem cells are analogous to normal organ and tissue stem cells, except they promote the renewal tumors. Targeting them specifically has been proposed as the newest key to eliminating cancers. It turns out, though, that cancer stem cells are just as elusive and hard to identify and quantify as normal tissue stem cells. So, this new field of cancer treatment is struggling to find successes.

Technologies for producing and quantifying natural organ and tissue stem cells are only just arriving on the scene. Their continued development promises a sea change in how stem cells are regarded for drug discovery.

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AsymmetrexIntroduction to Stem Cell Basics