Diabetes and Stem Cells—A 10-year Perspective

We are approaching the 10th anniversary of the isolation of human embryonic stem (huES) cells,¹ a seminal breakthrough that promptly germinated into one of the most prolific fields in recent scientific history. Concepts such as ‘regenerative medicine’ or ‘stem cell therapies,’ so commonly used today, did not start to appear in the scientific literature until the late 1990s. Although stem cell transplantation had been in clinical use for several decades for bloodrelated disorders, the notion that totally plastic, indefinitely expandable cells could be used as building blocks for the in vitro regeneration of any tissue was nothing less than revolutionary. Until then, and despite reports of ES cells obtained from many species,^2–4 it is as though we had not envisioned applications for these singular cells other than to create animal models for human diseases, increase livestock output, or improve the production of therapeutic proteins from transgenic animals. The feeling of unexpectedness that saluted the birth of this new field is reflected in the fact that 1998 marked the starting point not only of huES cell research, but also of a sudden interest in adult stem cells as an alternative source of tissues. After all, the procurement of ES cells from human and non-human primates had been hampered by technical difficulties up to that point, but the technology necessary to expand most adult stem cells was already in use a decade ago. Why had we not been pursuing the idea of using adult stem cells for medical purposes until Thomson and colleagues came up with the first embryonic stem cell lines? Be that as it may, a new field was born as the result of the confluence of disciplines as diverse as embryology, immunology, cell biology, and transplantation surgery.

Ten years later, the promise of this new field is evidenced by the use of several types of adult stem cells in clinical trials for a variety of conditions, including Crohn’s disease,⁵ myocardial infarction,⁶ and graft-versus-host disease.^7,8 New applications of autologous bone marrow transplantation are currently being developed either to tackle autoimmunity^9–11 or to induce regeneration in diseases such as diabetes.¹² Since they are still experimental, it is too early to determine whether or not these therapies will eventually change the state of the art in treating these conditions. Also (in what represents a reversion of the usual ‘bench to bedside’ directionality), once these therapies prove safe and effective, we must investigate the mechanisms behind the potential action of the transplanted cells. Do they work by differentiating into the types of cells that were damaged, or—as suggested by preliminary evidence—merely by flooding the damaged tissues with trophic signals that aid in self-regeneration? We can afford to answer these questions after the trials because, in the context of their proposed applications, most adult stem cells are relatively safe. This course of action is not possible with huES cells, and this is the only reason why they seem to lag behind their adult counterparts in terms of clinical applicability. The very same property that makes huES cells superior to other stem cells (i.e. their ability to be expanded indefinitely) is also a cause of concern because of the risk that some non-differentiated escapees may give rise to teratomas in vivo. Some groups have approached this problem by screening the number of undifferentiated cells present in each transplantable preparation. Their reasoning is that, if this number is below the threshold known to produce tumors in immunodeficient mice, these preparations should be considered safe for clinical use.¹³ This method, however, is not foolproof. First, not even the best cell-sorting techniques can ensure a 100% depletion of a rare subset of cells in a population. Second, the above threshold has been determined empirically. In theory, even a single non-differentiated cell could potentially develop into a tumor. Finally, it does not take into account the risk of de-differentiation after transplantation.¹⁴ This is why other groups have addressed this problem by integrating ‘suicide genes’ into ES cells. These elements sensitize ES cells to specific pro-drugs, which can be either added to the culture medium in vitro or administered to the recipient in vivo. The proteins encoded by these exogenous genes will react with the pro-drug and convert it into a toxic compound, which will subsequently kill the cell.^15–19 A drawback of this strategy is that if teratomas were to form in vivo due to de-differentiation of implanted cells, the use of the pro-drug would result in the destruction of the entire graft (see Figure 1). At any rate, the escape of undifferentiated cells is only one of the ways in which an embryonic stem cell may become teratogenic. Less attention has been paid to a much subtler risk: the accumulation of genomic instabilities as a result of long-term culture. Initial reports about the karyotypic stability of huES cells^1,20–22 have been recently revisited in view of the observation that the adaptation of these cells to prolonged in vitro culture does indeed favor the development of chromosomal aberrations.²³ The unequivocal similitude between in vitro proliferative adaptation and malignant transformation²⁴ warrants additional studies to assess the overall safety of huES cell-based therapies.