Stem cells derived Beta-cells encapsulated with a newly developed alginate analog are capable of producing insulin to sustain normal blood glucose
In a previous narrative in this blog we reported on a paper by Dr. Melton and co-workers (see PART 4 “In vitro preparation of Beta cells” at this blog describing a procedure they developed for the production of large amounts of human stem cells derived insulin producing β-cells (herein referred to as SC-β cells). When the SC-β cells were implanted directly into mice that were previously rendered diabetic by treatment with a substance called streptozotocin, the SC-β cells produced sufficient insulin to restore and maintain normal blood glucose levels in these animals. These results raised excitement and the hope that someday SC-β cells could be directly transplanted in patients with T1D. However, a direct transplant of SC-β cells in humans is not possible at the present time as issues such as immune attack by the host and possible cancer formation remain to be solved (Footnote 1). While waiting for medical advancements that will allow direct transplantations of SC-β cells directly into patients, several groups have been working to encapsulate pancreatic islets (cells that harbor β cells) in devices equipped with semi-permeable membranes to protect them from the attack of the host immune system.
Two biotechnology companies have already started Food and Drug Administration approved clinical trials with pancreatic islets (see PART 6 “Islets encapsulation to avoid auto- and allo-immunity” at this blog. Hopefully, we will have some information about these clinical trials sometime in 2016. The potential issues that the trials will clarify relates to the symbiosis (Footnote 2) between the patient and the transplant. In other words, will the host immune system attack the device by a process referred to as the Foreign Body Response (FBR) since the device is a foreign object? And is the host able to send sufficient oxygen and nutrients through the device’s membrane to allow the β cells inside the device to survive and produce insulin in response to glucose? (Footnote 3).
Given its potentiality in treating T1D, but also the issues associated to it, the encapsulation of insulin producing cell technology, is in a continuous development.
Two recent papers (References 1, 2, 3) report new β-cells’ encapsulation technology and its successful application to T1D animal models.
The first paper (Reference 1) relates to the development of biomaterials able to escape the Foreign Body Response when implanted in a host. To accomplish this, these investigators selected alginate as the starting biomaterial for chemical modifications. Alginate derivatives (or analogs) have been extensively used in regenerative medicine, especially to regenerate tissues and to implant scaffolding, because they have very interesting biological, physical, and chemical properties (Footnote 4). These investigators (Reference 1) chemically modified the alginate to generate nearly 800 alginate analogs; testing every one of them (without SC-β-cells) in animals (as small as mice and as big as non-human primates) to evaluate the Foreign Body Response to these foreign entities by the hosts. They identified three alginate-derived triazole-containing analogs with highly decreased Foreign Body Response by their hosts over the 6-month period of the experiments. Their finding of some promising alginate-derived triazole-containing analogs led to the work described in the second paper (Reference 2).
In the work described in the second paper (Reference 2), the investigators selected one of the three analogs and made micro-spheres out of it for encapsulation of SC-β cells (obtained by Dr. by Douglas Melton and colleagues). The micro-spheres harboring the SC-β cells were then implanted intraperitonally into mice referred to as C57BL/6J that were rendered diabetic by the use of streptozotocin. They used the C57BL/6J mice strain because these mice produce a strong Foreign Body Response and fibrosis similar to those observed in human patients. The study was designed to evaluate the safety and efficacy of this technology in producing insulin to sustain normal blood glucose in these animals. Indeed, the encapsulated SC-β cells implanted in the C57BL/6J mice immediately started producing insulin in response to blood glucose levels and maintained normal blood glucose for the length of the study that was 174 days. Also levels of C-peptide, a demonstration of insulin production by β cells, were comparable to those of normal (non diabetic) mice. Interestingly, they found that the 1.5 millimeter diameter micro-spheres were the best size to mitigate the action of the Foreign Body Response and to foster and maintain normalized blood glucose levels.
In conclusion, these scientists have shown that they have discovered an alginate analog that has both a relatively low Foreign Body Response, and can shield β cells placed inside it from the host immune attack thus allowing them to produce sufficient insulin capable of sustaining long-term (174 days) normal blood glucose in a mice model of T1D. These are of course very interesting results, and we hope that further studies in animal models would confirm both safety and efficacy of this technology to allow clinical studies with patients; however, some caution is needed as the scientific literature has shown over and over that treatments that have been safe and very efficacious in mice have not worked well in humans.
1. Major issues include SC-β cells safety when transplanted in humans, e.g., do they induce cancer or other undesired effects? SC-β cells are allogeneic cells (cells that come from another person) and their transplant would trigger both the host immune system response against these foreign entities (the so-called graft-versus-host disease or GVHD), and the same auto-immune attack that caused the disease in the first place; and even if the SC-β cells could be derived from the same patient (see PART 4 “Induced pluripotent stem cells (or iPS cells or iPSCs)” at this blog the implanted SC-β cells would still undergo the same autoimmune attack that caused the disease in the first place. The GVHD and auto-immune issues demand that patients receive immunosuppressive drugs for the rest of their lives.
2. Symbiosis is defined as the interaction between two different organisms living in close physical association, typically to the advantage of both.
3. Some of the potential issues that the trials will hopefully clarify are: (1) how efficiently blood capillaries will be able to form around the device to provide nutrients and oxygen for the islets to survive and function; (2) the semi-permeable membrane allows insulin crossing, but how efficiently will prevent the entrance of proteins such as antibodies and pro-inflammatory cytokines that, once inside the device, could promote islets deaths; (3) how well are the encapsulated islets able to mimic their natural counterparts in responding to raising glucose levels by releasing the correct physiological amounts of insulin; (4) how often the implant needs to be replaced as deposition of both fibrotic material around the device and waste inside it will occur overtime; (5) is the immune system going to attack the device by a process referred to as the Foreign Body Response (FBR) since it is a foreign object ?
4. Alginate is a naturally occurring anionic (negatively charged) and hydrophilic (water loving) polysaccharide (a large molecule formed by a long chain of simple sugars such as glucose and fructose linked together). It is mainly derived from brown seaweed and bacteria and is very abundant. Alginate analogs have been extensively used in regenerative medicine especially to regenerate tissues and to implant scaffolding. They make good semi-permeable membrane allowing glucose, nutrients, and oxygen to go inside the membrane and insulin and some toxic waste products to flow out of it; and alginate semi-permeable membranes separate and protect their enclosed β-cells from a direct deadly contact with cells of the immune system. Moreover, alginate analogs are good hosts for cells because they are capable of sustaining their normal physiological functions, have similarities to the host cells extracellular matrix, are biocompatible with the host, have good mechanical strength, and can be chemically modified. The latter feature has been exploited by many scientists (including those in these two papers) to generate huge varieties of alginate analogs.
1.Vegas AJ, Veiseh O, Doloff JC, Ma M, Tam HH, Bratlie K, Li J, Bader AR, Langan E, Olejnik K, Fenton P, Kang JW, Hollister-Locke J, Bochenek MA, Chiu A, Siebert S, Tang K, Jhunjhunwala S, Aresta-Dasilva S, Dholakia N, Thakrar R, Vietti T, Chen M, Cohen J, Siniakowicz K, Qi M, McGarrigle J, Lyle S, Harlan DM, Greiner DL, Oberholzer J, Weir GC, Langer R, Anderson DG. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat Biotechnol. 2016 Jan 25. doi: 10.1038/nbt.3462. [Epub ahead of print]
2. Vegas AJ, Veiseh O, Gürtler M, Millman JR, Pagliuca FW, Bader AR, Doloff JC, Li J, Chen M, Olejnik K, Tam HH, Jhunjhunwala S, Langan E, Aresta-Dasilva S, Gandham S, McGarrigle JJ, Bochenek MA, Hollister-Lock J, Oberholzer J, Greiner DL, Weir GC, Melton DA, Langer R, Anderson DG. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med. 2016 Jan 25. doi: 10.1038/nm.4030. [Epub ahead of print]
3. The work described by papers (1 and 2) was a collaborative effort by numerous scientists at various academic institutions across USA, and was in part, supported by the JDRF, the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the Tayebati Family Foundation, and these investigators academic institutions.