Stem cell therapies

Over the last decade, few (if any) topics in type 1 diabetes research have attracted more attention, conveyed a larger sense of promise, and – as some might argue – provided more 'hype' than the notion of stem cell therapies. Indeed, stem cell therapies have not only been the subject of significant effort in terms of scientific discovery but in addition, one of political debate, extensive financial investment, controversy over intellectual property rights, battles over ethics, morality and religion, and more. Although the road that has brought us to the present state of affairs has been long and hard, type 1 diabetes stands on the verge of seeing a variety of stem cell therapies entering clinical trials. Indeed, it is possible that the debate over embryonic versus adult stem cells may at long last find resolution (at least from the perspective of which has the most therapeutic potential) in the form of comparing results from clinical trials. Still, before the promise of stem cell therapies becomes reality, a series of hurdles must be overcome, and these are discussed below.

Why all the interest in stem cells?

Interest in stem cells as a potential treatment for type 1 diabetes is high, since such cells have the potential to alleviate the need for insulin injections.

The basic concept of cell replacement is not new; islet cell transplantation has been attempted for decades. However, there is a vast shortage of cadaveric islets to treat all type 1 diabetics.

Other sources of islet cells (e.g. cells obtained from other species, such as pigs) are not currently considered a practical option, due to the massive immune response that occurs when such cells are transplanted into humans, and the potential risk, however small, that transplantation across species might transfer disease into humans.

Since the immune system of patients that received islets from donors recognizes those transplanted cells as foreign, the donor islets will be rejected. In the most ideal situation, scientists would be able to grow or generate islet cells in the laboratory using cells derived from the patient.

Controlling rejection of tissues from another person with immunosuppressive drugs has clear benefits in terms of survival of transplanted tissues such as kidneys, hearts, and lungs, yet it comes at the cost of potentially serious drug-associated complications.

Stem cells derived from the same individual with type 1 diabetes would avoid the need for immunosuppressive drugs when replaced in the body. This would not provide a complete solution, however, since type 1 diabetes is caused by autoimmunity, and the new cells would risk destruction in the same way as the original pancreatic beta-cells. Some degree of immune therapy to protect against autoimmune is therefore likely to be required.

What are stem cells?

The definition of stem cells varies, but is generally applied to lines of relatively unspecialised cells that are capable of dividing (expanding) to large numbers, while retaining the potential to acquiring more specialised (differentiated) characteristics.[1] For example, a stem cell could be forced to become an islet cell, brain cell, heart cell, liver cell, and so forth. Once differentiated, the stem cell-derived line should be capable of stable replication, without further change in their cellular type, to provide a continuous supply of identical cells. Adults naturally retain a population of stem cells that are needed to provide an ongoing supply of replacement cells for the body; these are multipotent (i.e. potentially capable of differentiating into a limited variety of specialized cell types). Multipotent cells are recruited to replace damaged or old tissue.

Embryonic stem cells

Following conception, a fertilised egg divides into what essentially is a mass of stem cells. At the point where the egg has divided into more than 250 cells, each cell is considered to represent an embryonic stem cell (commonly referred to as an ESC).[2] These then go on to differentiate into the approximately 200 different types of specialised cells that make up the adult body, dividing and developing into specific cell types along paths prompted by the expression, or lack of expression, of specific genes. This being said, not all embryonic stem cells are equal. One form, the pluripotent stem cell, has the potential to differentiate into all cell types that make up the body. Other forms of embryonic stem cells known as multipotent stem cells are more limited in their developmental potential. For example, cells on the pathway to develop bone can develop various bone cells, but not pancreatic beta-cells. Human embryonic stem cells
Human embryonic stem cells

Discovery of these principles represented a major scientific feat, since it enabled investigators to direct significant efforts into identifying the genes and molecular stimulators responsible for generating beta-cells from stem cells. It should, however, be noted that the molecular stimulators, genes, and pathways involved in this process have been subject to a remarkable degree of controversy in recent years.

Academic controversy has been matched by intense competition between the investigators and biotechnology companies in the area. In recent years, three companies (Geron, BetaLogics and ViaCyte) have been considered leaders in these efforts, although Geron recently withdrew from this specific effort. For motives that range from the academic to financial level, all parties are in a race to use embryonic stem cells to develop some form of immature beta-cell that can mature into glucose-responsive, insulin-producing cells.

Recent reports suggest that this notion is close to becoming a reality. Indeed, when such cells were transplanted into mice with diabetes, the blood glucose levels dropped, and in some cases, the diabetes was actually cured. These studies also identified a particularly dangerous complication: teratomas. A teratoma is a tumour derived from multiple embyronic tissues, and may be benign or malignant. It has been hypothesised that their appearance following embryonic stem cell transplantation occurs because the preparation was contaminated by stem cells that were not yet fully differentiated into insulin-producing cells.

This emphasizes the need to develop procedures for improved purification of the desired cell types, and a potential need for some sort of 'barrier' device (e.g. a pouch or container) that could readily be removed if harmful events occur. Other investigators have focused on avoiding immune responses to these cells, for example using a container as suggested above to 'quarantine' these cells from the immune system, and thus avoid their immune destruction. If the differentiated cells were to be placed into a container with pores that are large enough for glucose to go in and insulin to get out, but small enough to keep the immune system’s cells and antibodies out, the transplanted cells would be safe from immune destruction. This approach would have 2 major advantages: first of all, patients could receive cells from donors without having to use immunosuppressants to prevent allo-rejection. Second, the autoimmune response that destroyed the patient’s beta-cells in the first place is prevented from happening again. When using such an encasement, it might actually be better to use cells that are not from the patient; if the device happens to break open (for instance by accident or because of contaminating stem cells that develop into growing teratomas, which puts so much strain on the device that it cracks), the patient’s own immune system would clean up the implanted cells right away. Furthermore, if the device gets encapsulated over a long period, it could easily be replaced with a fresh container.

Despite growing optimism, clinical embryonic stem cell therapy remains a distant option. Further requirements are better understanding of the reason why native islet beta cells are in close proximity to other islet endocrine cells such as glucagon producing-alpha cells, and developing means to scale-up cellular production to enable many patients with to be treated. In addition, as noted previously, stem cells should ideally be generated from self tissues, and with embryonic stem cells this is of course not possible. Hence, better ways of matching embryonic stem cells with a potential recipients are required. To this end, more recently, a great deal of enthusiasm has been generated by the concept of induced pluripotent stem (iPS) cells.

Induced pluripotent stem cells

One major limitation of cell or tissue transplantation is that cells normally carry on their surface a series of molecules that distinguish 'self' from 'non-self'. The chance that a potential recipient will find a perfect match within a population of donors is millions to one. For this reason, great enthusiasm surrounded the discovery in the mid-2000s of a method that turned differentiated cells back into undifferentiated stem cells, or 'induced pluripotent stem' cells (iPS cells).[3] iPS cells can be derived from adult tissues such as skin. By forcing the expression of specific stem cell-associated genes, Yamanaka and Gurdon were able to change differentiated cells back to an undifferentiated state. This scientific breakthrough won them the Nobel Prize in 2012[3] Like stem cells, iPS cells can be pushed to become insulin-producing cells that might be suitable for transplantation. Notably, scientists are currently investigating how to skip the step of turning differentiated cells into undifferentiated iPS cells first before differentiating these into insulin-secreting cells. They try to find ways to directly turn skin cells into islet cells using the same technique developed by Yamanaka and Gurdon. This direct conversion has been shown to be possible for making neuronal cells; it must be noted, however, that generating neuronal cells in the laboratory seems much easier than making insulin-producing beta-cells, because the latter procedure requires many, many more steps. Recently researchers have been able to safely and reproducibly generate insulin producing beta cells from pluripotent stems cells, which which Represents a monumental advancement in therapeutic applications for type 1 diabetes.[4]

Importantly these derived beta cells produced insulin to repeated glucose challenges over time. Despite this remarkable advance, significant hurdles need to be overcome before clinical testing of such cells as a treatment for type 1 diabetes can begin. For example, while these cells would avoid the problems of immune rejection, transplanting these cells in settings of type 1 diabetes could result in their destruction as a consequence of recurrent autoimmunity. Hence, some form of barrier, or the identification of drugs capable of avoiding autoimmunity, will be required. In addition, as with embryonic stem cells, significant improvements must occur in our ability to distinguish between normal and abnormal cells, since any genetically abnormal stem cell has the potential to become a tumor cell. Moreover, the procedure of generating patient-specific iPS cells is very labor-intensive, and currently impossible to apply to the millions of type 1 diabetics.

Companies offering stem cell therapies for treatment of diabetes are fake and dangerous!!

Beware that a lot of companies try to make money with the hype around stem cells. Especially in Asia, many companies exist that offer stem cell treatments for all kinds of diseases for large sums of money. Although it is understandable that patients become desperate and are willing to do (and pay) anything to get cured, they should realize that there is currently no stem cell-based treatment for diabetes! What most of these fake companies offer is the isolation of bone marrow cells from the patient, which they then re-inject after having grown them in the laboratory. These cells are not differentiated into functional insulin-producing cells; no matter what these companies claim. How do we know this? Because there is no scientific data to back up their claims. If there were, such achievements would be published in high-profile journals first and would be worth another Nobel Prize! Even worse, if these so-called clinics use (embryonic) stem cells, the danger of tumor development is extremely likely. Nobody wants to try out an unproven cure with a nearly 100% chance of getting cancer instead. Most of these companies charge several thousands of dollars for treatments and disappear a few years later. Don’t let those imposters become rich by getting money from desperate patients. Check out the trustworthy ISSCR website for more information:


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  4. ^ Pagliuca FW et al. Generation of functional human pancreatic β cells in vitro. Cell. 2014 Oct 9;159(2):428-39.


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