For anyone following the celebrity gossip of the stem cell field, you’ve probably come across one of our rising stars, the induced pluripotent stem cell (iPSC). Award winning and deemed to have loads of potential, each one of us can produce this type of cell. The buzz around iPSCs revolves around their ability to be generated from a patient’s own adult cells (e.g. fibroblasts or skin cells). Thus, they are genetically matched to the patient and can go on to differentiate into a myriad of therapeutically relevant target cells that won’t be rejected when transplanted. The implications are vast, and hundreds of research labs around the world are now working towards optimizing the best methods for iPSC production and differentiation.
Given that one of the main strengths of iPSCs is their immune-compatibility with patients, I couldn’t help but be initially taken aback by a recent article in Cell Stem Cell that quotes:
“While it is possible that clinical GMP-grade autologous iPSC lines could be derived on an individual basis, it seems unlikely that these will be used as a source for large numbers of patients in the near future, given the time and cost required to produce clinical GMP cell lines and to differentiate these into cells and tissues of clinical utility. It is likely, therefore, that a bank of allogeneic clinical GMP cell lines will be required to allow the ﬁeld to develop over the next few years…”
Allogeneic iPSCs? That’s like owning a smart phone without a data plan! A Bugatti in a city with a 50km/h speed limit! What’s the point? I feel bad for that car because its life purpose is being sadly under-realized.
Of course, behind every Cell paper is a team of very intelligent people (and, in this case, includes a Nobel Laureate) who know a lot more about a field than the rest of us, and so let me tell about why they suggest these iPSC banks.
Most people have some sense that when a cell or tissue comes from another person (called an “allogeneic” source), that graft will be rejected unless it matches up really well on what are called “Human Leukocyte Antigens” (HLAs; the Cell Stem Cell paper also provides a good background on this). Each cell exhibits numerous HLAs, each of which can drastically differ from person to person. Usually, when an organ is transplanted it is “mostly” HLA-matched to a patient, but it is very difficult to have a complete match in the absence of an identical twin. The result of partial matching is that the organ is not immediately rejected and can survive for many years with the patient on immunosuppressive drugs.
Creating an iPSC-based graft specific to a patient would obviate this problem of rejection, but creating each iPSC line is a time-consuming and expensive process that requires a lot of attention towards maintaining the purity and sterility of the cell lines. The authors thus argue that a cost-effective solution could be to create banks of iPSCs that include enough lines to partially match the majority of a population. Such cell lines would be created by sampling the genetic HLA make up of the population to evaluate the spectrum of HLA combinations that have to be covered. An international system of these banks could then be created.
The authors highlight a number of ethical and practical challenges that will have to be met for such a solution to be realized, including international cooperation, informed consent of donors, pre-cautions about infection, and guidelines surrounding release of incidental findings of a person’s genetic information, but nothing seems to be too debilitating.
So if you can look past the fact that the iPSCs may not be exactly matched to patients, the authors offer an interesting solution to maximizing the availability of iPSC therapies.
Can we look past HLA mismatch?
It could limit the types of therapies for which iPSCs are used. For example, would a diabetic give up insulin therapy for a partially matched pancreatic beta cell transplant, if he or she had to be on immunosuppressives long term? Would this be a more cost-effective solution? It really depends on the degree of matching these cell banks can achieve.
Undoubtedly, there will be a niche for even partially matched iPSCs. And they will have the advantage of being more readily available, since one can skip the whole step of collecting samples from a patient to generate patient-specific cell lines (this can take months).
I would like to also remind the reader of a lot of other fascinating research going on in the field of stem cells and transplant immunology. For example, tolerizing patients to allogeneic grafts by combined organ and hematopoietic stem cell transplantation (you could create an HSC bank to match the iPSC bank), as I’ve written about previously. It is also known that mesenchymal stem cells, which you read about a lot in the news, have immunopriviledged properties (are resistant to rejection), and studying the underlying mechanisms could lend powerful information to the field of stem cell/organ allotransplantation.
So while initially seeming counterintuitive, I’m now on board with the idea of allogeneic iPSC banks. Because they could be a readily available source of cell therapies for millions of people, and their shortcomings in immunocompatibility may become increasingly less important as other research in transplantation immunology progresses.
Turner M., Leslie S., Martin N., Peschanski M., Rao M., Taylor C., Trounson A., Turner D., Yamanaka S. & Wilmut I. & (2013). Toward the Development of a Global Induced Pluripotent Stem Cell Library, Cell Stem Cell, 13 (4) 382-384. DOI: 10.1016/j.stem.2013.08.003
Yi T. & Song S.U. (2012). Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications, Archives of Pharmacal Research, 35 (2) 213-221. DOI: 10.1007/s12272-012-0202-z
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