|Year : 2017 | Volume
| Issue : 1 | Page : 34-38
Stem cell-based approach in diabetes and pancreatic cancer management
Yi-Zhou Jiang1, Demeng Chen2
1 Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2 Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, CA, USA
|Date of Submission||13-Oct-2016|
|Date of Acceptance||17-Jan-2017|
|Date of Web Publication||23-Feb-2017|
Division of Oral Biology and Medicine, UCLA School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA 90095-1668
Source of Support: None, Conflict of Interest: None
Stem cell-mediated therapy is a promising strategy for treating pancreatic diseases such as Type-1 diabetes (T1D) and pancreatic cancers. Although islet transplantation has been reported to be an effective diabetes therapy, its worldwide application is extremely limited due to the shortage of donor islets and immune rejection problems. Stem cell-based approach for islet neogenesis in vivo could provide a promising alternative source of islets for treating diabetes. On the other hand, targeting the cancer stem cells could be very effective for the treatment of pancreatic cancers. In this review, we focused on the present progress in the field of adult pancreatic stem cells, stem cell-mediated strategies for treating T1D, and pancreatic cancer stem cells, while discussing of the possible challenges involved in them.
Keywords: Adult stem cells, cancer stem cells, diabetes, islet neogenesis, pancreatic cancer
|How to cite this article:|
Jiang YZ, Chen D. Stem cell-based approach in diabetes and pancreatic cancer management. Cancer Transl Med 2017;3:34-8
| Introduction|| |
Misregulated cellular function or cell growth often results in pancreatic diseases such as diabetes. Type-1 diabetes (T1D) is a disease characterized by the autoimmune destruction of insulin-producing beta-cells in the pancreas. Insulin injection can offer some temporary relief but is not the best therapy of diabetes because of the difficulty in determining the appropriate dose of insulin, associated with possible rejection. Successful islet transplantation has been proved effective in treating T1D., However, shortage of donor islets and immune rejection of heterogeneous tissue limit the widespread use of this method. Stem cell-based approaches have been studied well for tissue regeneration.,,,,, Stem cells for surrogate islets are the most promising method to solve this problem of islets limitation. The most direct and ideal way is to in vivo proliferate and differentiate the adult pancreatic stem cells (PSCs) into functional beta-cells. Extensive research has been performed to study the existence and function of the adult PSCs.,, However, there are still significant gaps in our knowledge, such as their precise location, cell surface markers, mechanisms involved in their proliferation, and differentiation, and even the existence of adult PSCs is still under controversy. On the other hand, misregulations of stem cell function in the pancreas often result in pancreatic cancers. Similar to normal stem cells, pancreatic cancer stem cells have unlimited self-renewal ability and are able to differentiate into many different cell types to maintain the growth and expansion of cancer tissues.,,, The pancreatic cancer stem cells are resistant to current cancer treatments such as chemotherapy and therefore targeting pancreatic cancer stem cells presents as promising strategy for pancreatic cancer treatment. In this review, we present a summary of recent advances in the adult PSCs and other stem cell-mediated therapeutics and discussed about possible challenges of the stem cells' approaches for diabetes and cancer therapy.
| Adult Pancreatic Stem Cell-Based Approach for Diabetes Therapy|| |
Adult stem cells in the islet
The pancreatic islets are one of the most vascularized organs of the body. There are mainly four types of cells in the islet: α, β, δ, and PP cells. The islet endothelium is richly fenestrated, to facilitate transendothelial transport of secreted hormones, has a unique expression of surface markers, and produces a number of vasoactive substances and growth factors., The adult pancreas has the ability to maintain the homeostasis of beta-cell regeneration in response to the physiological needs such as the requirement for increased beta-cells during pregnancy, obesity, or insulin resistance. Beta-cell mass in islet of the pancreas is dynamic, which is determined by the interaction between beta-cell mass expansion and reduction mechanisms. The renewed beta-cells might be derived from the following sources: neogenesis from precursor cells in the islet, neogenesis from ductal cells or exocrine pancreatic cells, or replication of existing mature beta-cells.
Stem cells in the islet have attracted much attention recently. There are some reports on the identification and expansion of pancreatic stem/progenitor cells residing inside the islet. Nestin, the intermediate filament protein that serves as a marker of neural stem cells, might be a possible but not specific cell marker of the adult PSCs. A distinct population of nestin-positive cells, nestin-positive islet-derived progenitor, residing in both rat and human islets has been identified and reported to be hormone-negative, multipotential immature cells that can proliferate extensively in vitro and can be induced to be insulin-producing cells. When transplanted into immunocompetent mice, either under the kidney capsule or by systemic injection, these nestin-positive stem cells can survive in engraftment and produce tissue chimerism to cross xenogeneic transplantation immune barriers. Thus, nestin-positive cells are proposed to be the precursors of differentiated pancreatic endocrine cells in the islet.
Apart from the nestin-positive cells, Petropavlovskaia and Rosenberg  reported that a small population of cells in the islet, positive for PDX-1, synaptophysin, insulin, glucagon, somatostatin, pancreatic polypeptide, alpha-fetoprotein, and Bcl-2 but negative for cytokeratin 19 and nestin, may serve as the progenitors contributing to the islet growth. In streptozotocin-treated mice, Guz et al. identified two types of presumptive progenitor cells in regenerating islets, one expressing Glu-2 and the other coexpressing insulin and somatostatin, demonstrating beta-cell neogenesis in adult islets. Evidence from in vitro cell culture system also supports the existence of adult PSCs in the islet. Most recently, Zou et al. have isolated and in vitro expanded the PSCs from the islet of both normal and T1D monkeys. These stem cells could spontaneously form islet-like clusters and can be further induced to be insulin-producing beta-cells with biological functions. A long-term (more than a year) culture of isolated islets, from both human and hamster, indicates that islet cells gradually transdifferentiate into ductal, acinar, and intermediary cells. Human islets can be maintained in vitro, in the culture conditions, over a long period of time at which they seem to transdifferentiate into exocrine cells and undifferentiated cells, which may be considered pancreatic precursor (stem) cells. In a study by Jamal et al., quiescent adult human islets were induced to undergo a phenotypic switch to highly proliferative duct-like structures and then converse to islet-like structures, which resembled freshly isolated human islets with respect to: the presence and topological arrangement of the four endocrine cell types, islet gene expression and hormone production, insulin content, and glucose-responsive insulin secretion.
One of stem cells' characteristics is the ability to clone itself. Seaberg et al. first reported the isolation of pancreas-derived multipotential precursors from both pancreatic islets and ducts. Using clonal analysis, they isolated the putative adult pancreatic precursors, representing a previously unidentified adult intrinsic pancreatic precursor population, which facilitates rapid progress toward an understanding of these cells' properties and gene information specifically expressed in this cell population.
Adult stem cells in the duct
Ductal cells of the pancreas form the epithelial lining of the branched tubes that deliver enzymes produced by pancreatic acinar cells into the digestive tract. In addition, these cells secrete bicarbonate that neutralizes stomach acidity. During development, epithelium of endodermal origin evaginates from the future duodenum area and invades the mesenchyme to form a complex branched network. Ductal cells of the pancreas have recently been under scrutiny for the identification of PSCs. In addition to normal renewal assay, several experimental systems to investigate the characteristics of these cells have been developed: pancreatic duct ligation, cellophane wrapping, pancreatectomy, genetically targeted destruction, or beta-cells destruction by streptozotocin, to prove the existence of stem cells in the pancreatic duct, which can proliferate and differentiate into beta-cells., For example, Peters et al. reported that the stem cell markers, c-Kit and nestin, as well as the transcription factors, PDX-1 and NKX2.2, are upregulated in compartments of the pancreas that are involved in islet cell neogenesis after duct ligation. In addition, confocal laser microscopy analysis showed that the nestin and PDX-1 are colocalized in a subset of cells, in small evaginations of the main duct, positive for the ductal cell marker, cytokeratin 19, which suggest that the double-positive cells for PDX-1 and nestin might be the important candidates for PSCs in adult rats. Furthermore, nestin-positive duct stem cells in the pancreas could be generated in adult pancreas by neogenic motivations, and they may differentiate into insulin-secreting cells. The intermediate filament vimentin might also be a marker of pancreatic precursor cells in the proliferating duct cells and could be used to investigate the concept of the dedifferentiation of fully matured duct cells during the process of the beta-cell neogenesis. The experimental systems to identify the possible stem cell markers in the pancreatic duct provide important guidance for the isolation and purification of the PSCs in the duct and possibly in other parts of the adult pancreas. Using the fluorescence-activated cell sorting technique, scientists have isolated the putative PSCs and further studied the characterization of their surface phenotype, thus advancing the therapeutic strategies for diabetes mellitus.
Invitro cell culture experiments also offer some evidence for beta-cells neogenesis from pancreatic ducts. When cultured with fetal mesenchyme, insulin-secreting cells can be generated by in vitro culture of preparations enriched in ducts from normal human pancreas or nonobese diabetic mice and those insulin-secreting cells can successfully reverse diabetes in vivo., Furthermore, the adult human pancreatic duct cells can be converted into insulin-expressing beta-cells by upregulating the expression of specific transcription factors essential for beta-cell differentiation (such as NeuroD/beta2, Pax4, Nkx2.2, Pax6, and Nkx6.1) through adenovirus Ngn3 transfection. It is worth mentioning that in many of these studies, the islet regeneration occurs close to ducts and duct-like structures in the pancreas. Furthermore, there is substantial evidence to support the hypothesis that the islet neogenesis in the mature pancreas might occur through cells in or associated with the ductal epithelium., Although we can not specify the exact characteristics, such as their resident position and the mechanisms involved in the pancreatic ductal stem cells such as function in the islet regeneration, the pancreatic ductal stem cells do hold significant potential for the stem cell approach of diabetes therapy.
Adult stem cells in the exocrine
In adult human, islets constitute 1%–2% of pancreatic tissue, leaving approximately 98% exocrine tissue as discard after islet isolation and purification. The limitation of the islets in the pancreas, the shortage of donor pancreas, and the loss during the course of islet isolation, result in the shortage of islets for the wide application of islet transplantation. The large amount of exocrine tissue in the pancreas would be an ideal source for the islet neogenesis provided that the pancreatic exocrine cells can be transdifferentiated into insulin-producing beta-cells. Hao et al. reported the nonendocrine-to-endocrine differentiation in adult human pancreas. In the study, a highly purified population of nonendocrine pancreatic epithelial cells (NEPECs) was cotransplanted with fetal pancreatic cells under the kidney capsule of immunodeficient mice, where the CK19 + NEPECs were found differentiated into insulin-producing beta-cells. The authors also proved that these insulin-producing beta-cells are not from beta-cell replication or cell fusion that could have explained the appearance of insulin-positive cells from a nonendocrine source such as NEPECs. Although the nature of the inductive factors in the fetal pancreatic cells is not known, their study did indicate the existence of the exocrine PSCs and updated our knowledge on the stem cells in the exocrine pancreas.
In previous studies, Baeyens et al. and Rooman et al. reported that acinar exocrine cells, isolated from adult pancreas, can dedifferentiate into duct-like cells, hepatocyte-like cells, and insulin-producing beta-cells. The primary rat pancreatic exocrine cells could be transdifferentiated into hepatocyte-like cells during 5 days culture in the presence of dexamethasone. The absence of cell proliferation, coexpression of albumin and amylase, and the expression of multiple liver-specific genes demonstrated a direct transdifferentiation of acinar cells to hepatocytic cells. In addition to the liver lineage cells, the pancreatic exocrine cells can also be differentiated into insulin-producing beta-cells through an acinar-to-islet conversion on duct ligation in vivo and treating with epidermal growth factor and leukemia inhibitory factor in vitro. The Notch signaling pathway is activated concomitantly, with changes in transcription factor expression, in pancreatic acinar cells that functions in the suppression of exocrine cell proliferation. Most importantly, a very similar change in the exocrine differentiation is observed in vivo when adult pancreatic tissue is injured and tissue remodeling occurs with all surviving exocrine, acinar, and ductal cells, differentiating similar to fetal or protophenotype. In conclusion, these observations support the notion of plasticity in the adult pancreas and that the exocrine cells can be reprogrammed to transdifferentiate into other cell types such as hepatocytes and insulin-producing beta-cells. This may make the pancreatic exocrine cells, a promising cell source for the islet regeneration.
However, the potential role of pancreatic exocrine cells in islet neogenesis is still a matter of debate. Evidence to support the proposal for transdifferentiation is lacking in most of other studies, and alternative explanations may be more attractive. For instance, selective cell death of exocrine cells and survival of the more robust contaminated islets and ductal cells may be the predominant mechanism at work in some cases. Stronger evidence (e.g., genetic cell tracking and clonal analysis) supporting the claim of exocrine cell differentiation is essential to further study the existence of and characterizing the exocrine PSCs, for their potential use in islet neogenesis.
| Other Stem Cell-Mediated Diabetes Therapy|| |
As discussed above, stimulating the adult PSCs for islet neogenesis or functional beta-cell restoration represents an ideal strategy for T1D therapy because of the limited immunorejection. However, other stem cells, such as mesenchymal stem cells, embryonic stem cells (ESC), and induced pluripotent stem cells (iPSCs), can serve as alternative source for diabetes therapy [Figure 1]a. A recent study has reported the generation of functional beta-cells from both ESCs and iPSCs, from both nondiabetic donors and diabetes patients. Using a well-defined differentiation protocol, they successfully generated large number of glucose-responsive beta-cells from stem cells. These stem cell-derived pancreatic beta-cells expressed cellular marker of beta-cells, showed functional features of mature beta-cells both in vitro and in vivo, and can control glucose levels in diabetic mouse models. Most importantly, using a similar approach, Millman et al. further generated functional beta-cells using iPSCs from T1D patients and revealed that these diabetic patients' iPSCs generated beta-cells are able to respond to glucose levels both in vitro and in vivo and prevent alloxan-induced diabetes in mice, demonstrating the promise that such stem cells carry in treating T1Ds. Indeed, recent clinical trials have suggested that stem cell-mediated therapy may be a viable and promising treatment option for T1D.
|Figure 1: Stem cell-mediated therapy for diabetes and pancreatic cancers. (a) Functional beta-cells derived from adult pancreatic stem cells or other pluripotent stem cells for diabetes treatment. (b) Specific inhibition of cancer stem cells for the pancreatic cancer treatment|
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| Targeting Cancer Stem Cells for Treatment of Pancreatic Cancers|| |
Stem cell-mediated regeneration of functional beta-cells using endogenous or exogenous adult stem cells is a promising therapeutic strategy for T1D treatment. However, one potential adverse effect of such stem cell-mediated therapy is tumor development. Indeed, injection of exogenous stem cells or misregulation of the endogenous stem cell population could potentially results in the transformation into cancer stem cells., Therefore, a better understanding of the molecular mechanisms of stem cell-assisted regeneration and their transformation is essential for safer stem cell-mediated T1D therapy and without triggering development of pancreatic cancer.
Cancer stem cells are a special group of cancer cells that possess the characteristics very similar to normal stem cells. Specifically, cancer stem cells have unlimited self-renewal ability and the potential to differentiate into many different cell types to maintain the growth and expansion of cancer tissues.,,, Although cancer treatments such as chemotherapy can kill most of the cancer tissues, cancer stem cells are resistant to most treatments and often result in relapse of cancers after treatment. Therefore, targeting cancer stem cells could potentially kill the root of cancers and result in a complete cure of the disease. Here, we discuss the characteristics of pancreatic cancer stem cells and their potential as therapeutic targets for the treatment of pancreatic cancer.
Similar to adult PSCs, pancreatic cancer stem cells also express certain cellular markers, which are valuable in their identification and characterization. Li et al. identified a subpopulation of pancreatic cancer cells that express CD44 +, CD24 +, and ESA + markers and are highly tumorigenic in nature with many stem cell properties including potent self-renewal and differentiation abilities. The CD44 + CD24 + ESA + cancer stem cells account for 0.2%–0.8% of all human pancreatic cancer cells and are essential in the maintenance of cancer. Other pancreatic cancer stem cells, positive for markers such as CD133, ALDH, DclK1, and Lgr5, are also identified.,, Cells expressing these markers exhibit stem cell characteristics and are found resistant to standard chemotherapy and radiotherapy. The increased expression of these cancer stem cell markers is often associated with poor patient survival and increased chances of relapse after standard treatment. The pancreatic cancer is a heterogeneous tissue that composed of multiple different cell types, which provides a microenvironment (niche) for the pancreatic cancer stem cells to flourish. The cells in the pancreatic tissue express aberrant oncogenic pathways, such as WNT, Notch, and Shh signaling, to control the self-renewal and differentiation of pancreatic cancer stem cells essential for the tumor growth.,,, In addition, pancreatic cancer stem cells are associated with cancer metastasis through epithelial to mesenchymal transition,, further supporting the critical role of pancreatic cancer stem cells in regulation of pancreatic cancer growth and progression.
Targeting pancreatic cancer stem cells abolished their self-renewal and differentiation abilities and resulted in very effective inhibition of cancer growth. Recent discovery revealed that the combined inhibition of hedgehog/GLI and mechanistic target of rapamycin could efficiently eliminate pancreatic cancer stem cells and suppress pancreatic cancer growth, providing strong evidence that therapeutic strategies to inhibit cancer stem cells are very promising in effectively treating pancreatic cancer [Figure 1]b.
| Conclusion|| |
Although there has been great progress in the field of adult PSCs and pancreatic cancer stem cells, many issues/controversies still remain to be resolved, before their clinical application. Some important challenges include: (1) locating and characterizing the adult PSCs; (2) understanding the underlying mechanisms in the proliferation and differentiation of adult PSCs; (3) improving the efficiency of islet neogenesis from the stem cells as the present methods cannot produce sufficient islets for the transplantation; (4) the true beta-cell nature of the insulin-producing cells differentiated from stem cells is still under debate, hence needs further characterization; and (5) although many cellular markers have been identified for the pancreatic cancer stem cells, their specific and effective targeting is still a challenge. Overall, the stem cell-based approach holds great promise in the treatment of pancreatic diseases, such as T1D and pancreatic cancer.
Financial support and sponsorship
Conflict of interest
There are no conflicts of interest.
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