© 2013 John Wiley & Sons A/S.
Clin Transplant 2013: 27 (Suppl. 25): 30–33 DOI: 10.1111/ctr.12153
Alternatives to islet transplantation: future cell sources of beta-like cells Bruns H, Schultze D, Schemmer P. Alternatives to islet transplantation: future cell sources of beta-like cells.
Helge Bruns, Daniel Schultze and Peter Schemmer
Abstract: Cell transplantation is a treatment option for diabetes, metabolic liver disease in children, and leukemia. Except for the latter indication, solid organ transplantation is one of the available therapies but can be replaced by cell transplantation. However, due to the limited amount of cells that can be transplanted and due to rejection, results of cell transplants are still inferior to solid organ transplantation; there is a general shortage of donor organs, and cell isolation is limited to organs which cannot be transplanted as a whole for anatomic reasons. Therefore, alternatives to islets and beta cells are needed. There are some cells which can be generated from the recipient and would not be rejected; still, immunosuppression would be required to prevent reoccurrence of type I diabetes unless durable tolerance to beta cells could be induced. Generating beta cells for transplant from the recipient would help to overcome the lack of available organs. Moreover, understanding the underlying mechanisms of differentiation of these cells into beta-like cells would deepen our understanding of both pathophysiology and development of diabetes mellitus type I. This article examines embryonal stem cells, induced pluripotent cells, mesenchymal stromal cells, and hepatocytes as potential alternatives to beta-cell transplantation.
Diabetes mellitus is becoming an increasing problem worldwide; in 2004, more than 220 000 000 patients were affected (1). By 2030, the number of patients suffering from diabetes mellitus will have almost doubled (2). In type I diabetic patients, treatment with exogenous insulin is the most established and most effective standard therapy; but even with close monitoring of blood glucose levels and in highly compliant patients, secondary diseases, such as renal insufficiency, retinopathy, and diabetic feet, are common after years of treatment. These secondary diseases are not only a threat to the patient’s health, but also a relevant cost driver in healthcare systems. Thus, alternatives to insulin therapy, such as islet transplantation and pancreatic transplantation with or without simultaneous kidney transplantation, have been investigated and are available therapies for some patients with instable blood glucose levels. The effectiveness of both therapies lies in the re-establishment of insulin production; both are potentially curative treatment options limited to the access to donor organs. Further, success is limited by the need for lifelong immunosuppression and rejec-
30
Department of General and Transplant Surgery, Ruprecht-Karls-University, Heidelberg, Germany Key words: beta cells – diabetes mellitus – islet transplantation Corresponding author: Peter Schemmer, MD, Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Tel.: +49 (0)6221/56-6110; Fax: +49 (0)6221/56-4215; e-mail: [email protected]. de Conflict of interest: No conflicts of interest exist. Accepted for publication 20 December 2012
tion of the transplanted organ and islets in the long term. By 2004, more than 23 000 pancreas transplantations had been performed worldwide (3), and to date, more than 750 patients have received islet transplants (4). Given the high number of diabetic patients, there is a great demand for organs and cells; but it would not be reasonable to transplant every patient suffering from type I diabetes, as insulin therapy is an effective treatment with very few side effects; after transplantation, side effects of immunosuppressive therapy would supersede side effects of ineffective insulin treatment and high blood glucose levels in the majority of patients. Moreover, transplantation is a curative, but not definitive treatment of diabetes; in most patients, the demand for insulin relapses some time after transplantation due to rejection of the transplanted organ or the transplanted islets. Compared to whole organ transplants, islet transplantation seems to be less invasive; the cells and islets can be infused via a catheter placed in the portal vein. Transplantation of islets via the portal vein puts them in the place where they are most effective: into the liver. Here, the cells can
Alternatives to islet transplantation respond directly to blood glucose levels depending on the first pass of oral nutrition. This is a faster and more exact response than the injection of insulin depending on peripheral blood glucose levels. While islet transplantation is an effective treatment, this is limited to the number of available cells and islets; in the majority of patients, islets from multiple donors have to be used to gain a sufficient number of beta cells for treatment (5). Due to rejection of the islets, cell transplantation needs to be performed repeatedly, and patients require immunosuppression (6). Thus, alternatives to replacing beta cells have been investigated; these may only be available in the future, but investigating these alternatives and transdifferentiation of alternative cell sources will deepen our understanding of the development of type I diabetes and could help to not only treat, but also prevent this disease in the long term. Alternatives to islets and beta cells
There are various cell types that, at least in vitro, can differentiate into cells that respond to glucose stimulation with the secretion of insulin and could function as beta-cell substitutes; embryonal stem (ES) cells (7), induced pluripotent stem (iPS) cells (8), mesenchymal stromal cells (MSC) (9), and hepatocytes (10) can differentiate into cells that mimic beta-cell behavior. iPS cells, MSCs, and hepatocytes are available from patients suffering from type I diabetes and could thus be transplanted without the need for further immunosuppression or the risk of rejection, which makes these cells a tempting potential alternative to exogenous insulin treatment. Embryonal stem cells
ES cells show great plasticity and can differentiate into all lineages; thus, it is not surprising that these cells can form beta cells as well. More than 10 yr ago, Assady et al. demonstrated the spontaneous differentiation of ES cells into insulin-producing cells (7). Spontaneously, ES cells seem to be optimal candidates as these cells can be stored until needed, easily expanded, and differentiated in vitro. However, there are major limitations that, besides ethical considerations, have to be kept in mind: patients might, for instance, need immunosuppression to prevent rejection as these cells would be foreign to the recipients’ immune system – again, the side effects of high blood glucose levels would be replaced by the side effects of immunosuppression – and, moreover, cells would be rejected after some time, even with immunosuppression. Due to
these potential drawbacks as well as ethical considerations, these cells seem, in fact, to be suboptimal candidates for future beta-cell replacement therapies. Induced pluripotent stem cells
The limitations of ES cells can be overcome using iPS cells; there are no ethical considerations to be taken into account. These cells can be generated from somatic cells by introducing Oct3/4, Sox2, Klf4, and c-Myc and share properties with ES cells (11). Moreover, iPS cells would be available from the future recipient, and there would, thus, be no need for immunosuppression after transplantation. In 2010, Alipio et al. demonstrated the reversal of hyperglycemia in vivo using these cells. After reprogramming skin fibroblasts to iPS cells, cells were differentiated using an established protocol for ES-cell differentiation (8). The cells generated produced insulin as a response to glucose stimulation in vitro, and in a mouse model of type II diabetes, transplantation of these cells ameliorated hyperglycemia (8). In another model, blood glucose levels were normalized after cell transplantation in mice with streptozotocin-induced diabetes (12). Mesenchymal stromal cells
MSC can easily be extracted from various tissues (e.g., bone marrow and adipose tissue, among other sources) and can, depending on cytokines and cell–cell interactions, differentiate into various cell types that form bone, cartilage, adipose tissue, and hepatocytes (13–17). In 2011, Phadnis et al. demonstrated that human bone marrow (hBM)derived MSC can differentiate into endocrine pancreatic cells (9). In vivo, secretion of human C-peptide was present after transplantation of these cells into pancreatectomized and streptozotocin-induced diabetic mice; using transplantation of hBM-MSCs, normoglycemia could be maintained (9). In recent clinical trials, the potential of these cells in treating type I (18) and type II (19) diabetes was demonstrated. Vanikar et al. isolated MSCs from adipose tissue, differentiated them into insulin-producing cells and performed cotransplantation with cultured bone marrow cells in type I diabetic patients (18). HbA1c levels decreased, less insulin was needed, and C-peptide serum levels increased in these patients. In another clinical trial in type II diabetic patients, transplantation of placenta-derived MSCs lead to increased C-peptide levels as well as the decreased need for insulin (19). Taken together, the easy availability of MSCs, successful early clinical trials, and promising in vitro
31
Bruns et al.
and in vivo experiments render these cells a promising candidate for transplantation-based therapies to overcome diabetes.
ment of alternative treatments of insulin-dependent diabetes. Conclusion, criticism, and outlook
Liver-derived cells
Both beta cells and hepatocytes share a common progenitor cell (20). It has been shown that wnt and shh signaling are central factors that decide the fate of these cells (21), but it is unknown whether this is a reversible process. There are indications from in vitro and in vivo models that at least some cells keep the flexibility to differentiate from one cell type into the other; more than 20 yr ago, Reddy et al. demonstrated the existence of a cell type that persists in the pancreas and, in a copper-deficient diet, differentiates into cells of hepatic lineage (22). In a rodent model, copper deficiency for seven to nine wk lead to the depletion of pancreatic acinar cells and, after reintroduction of a normal diet, to the generation of cells of hepatic lineage in the small pancreatic ductules (22). These cells shared morphological properties with hepatic oval cells; in the induced hepatocytes, markers such as albumin, carbamoylphasphate synthase-I, and glutamine synthase were present (22). This indicates the flexibility of adult tissue specific stem cells and seems likely that this transdifferentiation can happen in the other direction as well. Oval cells (OC) have been described as dormant adult hepatic stem cells and can differentiate into pancreatic endocrine hormone-producing cells (10) in vitro. Moreover, induction of OC proliferation using a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) ameliorated hyperglycemia after subsequent induction of diabetes using streptozotocin (STZ) (23). One of the major problems in these experiments is the generation of OCs; these cells are only available in sufficient number after strong toxic injury to the liver and remain dormant under normal circumstances (24). Consequently, some researchers have described these cells as being artificial; nonetheless, there are hints that OCs are present in human adult liver as well (25). While these liver-derived cells are not clinical option yet, there might be, at least concerning in vitro and in vivo studies, an alternative to adult OCs. In rats, cells that share some properties with OCs have been identified (26, 27). These cells can serve as a model for OCs and are available in great number; they can be isolated from developing livers and, in contrast to adult hepatocytes, proliferate in vitro, and can be expanded easily (28). Further investigation of these cells will lead to a deeper understanding of the relationship between the liver and pancreas and may ultimately lead to the develop-
32
It is promising that beta-like cells can be generated from the future recipient. iPS cells, MSCs, and liver-derived cells therefore seem to be potential candidates for future cell-based therapies of insulin-dependent diabetes mellitus. It is still not known whether transdifferentiated cells that mimic beta-cell behavior would undergo the same process that leads to the destruction of beta cells and the development of type I diabetes; there are not yet any data on the long-term efficiency of treatment with these cells. It seems likely that these cells could serve as real alternatives in insulin-dependent diabetes mellitus type II. Given that these cells can be generated from the recipients own resources and durable tolerance to beta cells could be induced in type I diabetic patients, there would no longer be any need for immunosuppression. The first clinical trials have been conducted successfully, and MSCs seem to be the current cell candidate of choice, but more in vitro and in vivo research is needed to fully understand the underlying mechanisms and to estimate the efficacy and safety of these treatment options. In the authors’ opinion, the cell-based therapy approach is worth investigating and would lead not only to novel therapies but also to new insights into cell differentiation, beta-cell development, and the immune system’s role in the development of diabetes and beta-cell replacement therapies. Acknowledgement The authors would like to thank Katherine Hughes for language editing.
References 1. World Health Organization. The Global Burden of Disease: 2004 Update. WHO, Geneva, Switzerland, 2008. 2. WILD S, ROGLIC G, GREEN A et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004: 27: 1047. 3. GRUESSNER AC, SUTHERLAND DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005: 19: 433. 4. MCCALL M, JAMES SHAPIRO AM. Update on Islet Transplantation. Cold Spring Harb Perspect Med 2012: 2: a007823. 5. TRUONG W, LAKEY JR, RYAN EA et al. Clinical islet transplantation at the University of Alberta – the Edmonton experience. Clin Transpl 2005: 153.
Alternatives to islet transplantation 6. SHAPIRO AM. State of the art of clinical islet transplantation and novel protocols of immunosuppression. Curr Diab Rep 2011: 11: 345. 7. ASSADY S, MAOR G, AMIT M et al. Insulin production by human embryonic stem cells. Diabetes 2001: 50: 1691. 8. ALIPIO Z, LIAO W, ROEMER EJ et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci USA 2010: 107: 13426. 9. PHADNIS SM, JOGLEKAR MV, DALVI MP et al. Human bone marrow-derived mesenchymal cells differentiate and mature into endocrine pancreatic lineage in vivo. Cytotherapy 2011: 13: 279. 10. YANG L, LI S, HATCH H et al. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci USA 2002: 99: 8078. 11. YAMANAKA S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 2012: 10: 678. 12. JEON K, LIM H, KIM JH et al. Differentiation and transplantation of functional pancreatic beta cells generated from induced pluripotent stem cells derived from a type 1 diabetes mouse model. Stem Cells Dev 2012: 21: 2642. 13. CAPLAN AI. Mesenchymal stem cells. J Orthop Res 1991: 9: 641. 14. PITTENGER MF, MACKAY AM, BECK SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999: 284: 143. 15. LANGE C, BASSLER P, LIOZNOV MV et al. Hepatocytic gene expression in cultured rat mesenchymal stem cells. Transplant Proc 2005: 37: 276. 16. LANGE C, BASSLER P, LIOZNOV MV et al. Liver-specific gene expression in mesenchymal stem cells is induced by liver cells. World J Gastroenterol 2005: 11: 4497.
17. LANGE C, BRUNS H, KLUTH D et al. Hepatocytic differentiation of mesenchymal stem cells in cocultures with fetal liver cells. World J Gastroenterol 2006: 12: 2394. 18. VANIKAR AV, DAVE SD, THAKKAR UG et al. Cotransplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: a novel therapy for insulin-dependent diabetes mellitus. Stem Cells Int 2010: 2010: 582382. 19. JIANG R, HAN Z, ZHUO G et al. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Front Med 2011: 5: 94. 20. GROMPE M. Pancreatic-hepatic switches in vivo. Mech Dev 2003: 120: 99. 21. ZARET KS, GROMPE M. Generation and regeneration of cells of the liver and pancreas. Science 2008: 322: 1490. 22. REDDY JK, RAO MS, YELDANDI AV et al. Pancreatic hepatocytes. An in vivo model for cell lineage in pancreas of adult rat. Dig Dis Sci 1991: 36: 502. 23. KIM S, SHIN J, KIM H et al. Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration. Lab Invest 2007: 87: 702. 24. BIRD TG, LORENZINI S, FORBES SJ. Activation of stem cells in hepatic diseases. Cell Tissue Res 2008: 331: 283. 25. SCHMELZER E, REID LM. EpCAM expression in normal, non-pathological tissues. Front Biosci 2008: 13: 3096. 26. FIEGEL HC, PARK JJ, LIOZNOV MV et al. Characterization of cell types during rat liver development. Hepatology 2003: 37: 148. 27. ZVIBEL I, MIRI B, EINAV H et al. Isolation, characterization and culture of Thy1-positive cells from fetal rat livers. World J Gastroenterol 2006: 12: 3841. € C et al. Cell growth and dif28. FIEGEL HC, BRUNS H, HOPER ferentiation of different hepatic cells isolated from fetal rat liver in vitro. Tissue Eng 2006: 12: 123.
33
Clin Transplant 2013: 27 (Suppl. 25): 30–33 DOI: 10.1111/ctr.12153
Alternatives to islet transplantation: future cell sources of beta-like cells Bruns H, Schultze D, Schemmer P. Alternatives to islet transplantation: future cell sources of beta-like cells.
Helge Bruns, Daniel Schultze and Peter Schemmer
Abstract: Cell transplantation is a treatment option for diabetes, metabolic liver disease in children, and leukemia. Except for the latter indication, solid organ transplantation is one of the available therapies but can be replaced by cell transplantation. However, due to the limited amount of cells that can be transplanted and due to rejection, results of cell transplants are still inferior to solid organ transplantation; there is a general shortage of donor organs, and cell isolation is limited to organs which cannot be transplanted as a whole for anatomic reasons. Therefore, alternatives to islets and beta cells are needed. There are some cells which can be generated from the recipient and would not be rejected; still, immunosuppression would be required to prevent reoccurrence of type I diabetes unless durable tolerance to beta cells could be induced. Generating beta cells for transplant from the recipient would help to overcome the lack of available organs. Moreover, understanding the underlying mechanisms of differentiation of these cells into beta-like cells would deepen our understanding of both pathophysiology and development of diabetes mellitus type I. This article examines embryonal stem cells, induced pluripotent cells, mesenchymal stromal cells, and hepatocytes as potential alternatives to beta-cell transplantation.
Diabetes mellitus is becoming an increasing problem worldwide; in 2004, more than 220 000 000 patients were affected (1). By 2030, the number of patients suffering from diabetes mellitus will have almost doubled (2). In type I diabetic patients, treatment with exogenous insulin is the most established and most effective standard therapy; but even with close monitoring of blood glucose levels and in highly compliant patients, secondary diseases, such as renal insufficiency, retinopathy, and diabetic feet, are common after years of treatment. These secondary diseases are not only a threat to the patient’s health, but also a relevant cost driver in healthcare systems. Thus, alternatives to insulin therapy, such as islet transplantation and pancreatic transplantation with or without simultaneous kidney transplantation, have been investigated and are available therapies for some patients with instable blood glucose levels. The effectiveness of both therapies lies in the re-establishment of insulin production; both are potentially curative treatment options limited to the access to donor organs. Further, success is limited by the need for lifelong immunosuppression and rejec-
30
Department of General and Transplant Surgery, Ruprecht-Karls-University, Heidelberg, Germany Key words: beta cells – diabetes mellitus – islet transplantation Corresponding author: Peter Schemmer, MD, Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Tel.: +49 (0)6221/56-6110; Fax: +49 (0)6221/56-4215; e-mail: [email protected]. de Conflict of interest: No conflicts of interest exist. Accepted for publication 20 December 2012
tion of the transplanted organ and islets in the long term. By 2004, more than 23 000 pancreas transplantations had been performed worldwide (3), and to date, more than 750 patients have received islet transplants (4). Given the high number of diabetic patients, there is a great demand for organs and cells; but it would not be reasonable to transplant every patient suffering from type I diabetes, as insulin therapy is an effective treatment with very few side effects; after transplantation, side effects of immunosuppressive therapy would supersede side effects of ineffective insulin treatment and high blood glucose levels in the majority of patients. Moreover, transplantation is a curative, but not definitive treatment of diabetes; in most patients, the demand for insulin relapses some time after transplantation due to rejection of the transplanted organ or the transplanted islets. Compared to whole organ transplants, islet transplantation seems to be less invasive; the cells and islets can be infused via a catheter placed in the portal vein. Transplantation of islets via the portal vein puts them in the place where they are most effective: into the liver. Here, the cells can
Alternatives to islet transplantation respond directly to blood glucose levels depending on the first pass of oral nutrition. This is a faster and more exact response than the injection of insulin depending on peripheral blood glucose levels. While islet transplantation is an effective treatment, this is limited to the number of available cells and islets; in the majority of patients, islets from multiple donors have to be used to gain a sufficient number of beta cells for treatment (5). Due to rejection of the islets, cell transplantation needs to be performed repeatedly, and patients require immunosuppression (6). Thus, alternatives to replacing beta cells have been investigated; these may only be available in the future, but investigating these alternatives and transdifferentiation of alternative cell sources will deepen our understanding of the development of type I diabetes and could help to not only treat, but also prevent this disease in the long term. Alternatives to islets and beta cells
There are various cell types that, at least in vitro, can differentiate into cells that respond to glucose stimulation with the secretion of insulin and could function as beta-cell substitutes; embryonal stem (ES) cells (7), induced pluripotent stem (iPS) cells (8), mesenchymal stromal cells (MSC) (9), and hepatocytes (10) can differentiate into cells that mimic beta-cell behavior. iPS cells, MSCs, and hepatocytes are available from patients suffering from type I diabetes and could thus be transplanted without the need for further immunosuppression or the risk of rejection, which makes these cells a tempting potential alternative to exogenous insulin treatment. Embryonal stem cells
ES cells show great plasticity and can differentiate into all lineages; thus, it is not surprising that these cells can form beta cells as well. More than 10 yr ago, Assady et al. demonstrated the spontaneous differentiation of ES cells into insulin-producing cells (7). Spontaneously, ES cells seem to be optimal candidates as these cells can be stored until needed, easily expanded, and differentiated in vitro. However, there are major limitations that, besides ethical considerations, have to be kept in mind: patients might, for instance, need immunosuppression to prevent rejection as these cells would be foreign to the recipients’ immune system – again, the side effects of high blood glucose levels would be replaced by the side effects of immunosuppression – and, moreover, cells would be rejected after some time, even with immunosuppression. Due to
these potential drawbacks as well as ethical considerations, these cells seem, in fact, to be suboptimal candidates for future beta-cell replacement therapies. Induced pluripotent stem cells
The limitations of ES cells can be overcome using iPS cells; there are no ethical considerations to be taken into account. These cells can be generated from somatic cells by introducing Oct3/4, Sox2, Klf4, and c-Myc and share properties with ES cells (11). Moreover, iPS cells would be available from the future recipient, and there would, thus, be no need for immunosuppression after transplantation. In 2010, Alipio et al. demonstrated the reversal of hyperglycemia in vivo using these cells. After reprogramming skin fibroblasts to iPS cells, cells were differentiated using an established protocol for ES-cell differentiation (8). The cells generated produced insulin as a response to glucose stimulation in vitro, and in a mouse model of type II diabetes, transplantation of these cells ameliorated hyperglycemia (8). In another model, blood glucose levels were normalized after cell transplantation in mice with streptozotocin-induced diabetes (12). Mesenchymal stromal cells
MSC can easily be extracted from various tissues (e.g., bone marrow and adipose tissue, among other sources) and can, depending on cytokines and cell–cell interactions, differentiate into various cell types that form bone, cartilage, adipose tissue, and hepatocytes (13–17). In 2011, Phadnis et al. demonstrated that human bone marrow (hBM)derived MSC can differentiate into endocrine pancreatic cells (9). In vivo, secretion of human C-peptide was present after transplantation of these cells into pancreatectomized and streptozotocin-induced diabetic mice; using transplantation of hBM-MSCs, normoglycemia could be maintained (9). In recent clinical trials, the potential of these cells in treating type I (18) and type II (19) diabetes was demonstrated. Vanikar et al. isolated MSCs from adipose tissue, differentiated them into insulin-producing cells and performed cotransplantation with cultured bone marrow cells in type I diabetic patients (18). HbA1c levels decreased, less insulin was needed, and C-peptide serum levels increased in these patients. In another clinical trial in type II diabetic patients, transplantation of placenta-derived MSCs lead to increased C-peptide levels as well as the decreased need for insulin (19). Taken together, the easy availability of MSCs, successful early clinical trials, and promising in vitro
31
Bruns et al.
and in vivo experiments render these cells a promising candidate for transplantation-based therapies to overcome diabetes.
ment of alternative treatments of insulin-dependent diabetes. Conclusion, criticism, and outlook
Liver-derived cells
Both beta cells and hepatocytes share a common progenitor cell (20). It has been shown that wnt and shh signaling are central factors that decide the fate of these cells (21), but it is unknown whether this is a reversible process. There are indications from in vitro and in vivo models that at least some cells keep the flexibility to differentiate from one cell type into the other; more than 20 yr ago, Reddy et al. demonstrated the existence of a cell type that persists in the pancreas and, in a copper-deficient diet, differentiates into cells of hepatic lineage (22). In a rodent model, copper deficiency for seven to nine wk lead to the depletion of pancreatic acinar cells and, after reintroduction of a normal diet, to the generation of cells of hepatic lineage in the small pancreatic ductules (22). These cells shared morphological properties with hepatic oval cells; in the induced hepatocytes, markers such as albumin, carbamoylphasphate synthase-I, and glutamine synthase were present (22). This indicates the flexibility of adult tissue specific stem cells and seems likely that this transdifferentiation can happen in the other direction as well. Oval cells (OC) have been described as dormant adult hepatic stem cells and can differentiate into pancreatic endocrine hormone-producing cells (10) in vitro. Moreover, induction of OC proliferation using a diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) ameliorated hyperglycemia after subsequent induction of diabetes using streptozotocin (STZ) (23). One of the major problems in these experiments is the generation of OCs; these cells are only available in sufficient number after strong toxic injury to the liver and remain dormant under normal circumstances (24). Consequently, some researchers have described these cells as being artificial; nonetheless, there are hints that OCs are present in human adult liver as well (25). While these liver-derived cells are not clinical option yet, there might be, at least concerning in vitro and in vivo studies, an alternative to adult OCs. In rats, cells that share some properties with OCs have been identified (26, 27). These cells can serve as a model for OCs and are available in great number; they can be isolated from developing livers and, in contrast to adult hepatocytes, proliferate in vitro, and can be expanded easily (28). Further investigation of these cells will lead to a deeper understanding of the relationship between the liver and pancreas and may ultimately lead to the develop-
32
It is promising that beta-like cells can be generated from the future recipient. iPS cells, MSCs, and liver-derived cells therefore seem to be potential candidates for future cell-based therapies of insulin-dependent diabetes mellitus. It is still not known whether transdifferentiated cells that mimic beta-cell behavior would undergo the same process that leads to the destruction of beta cells and the development of type I diabetes; there are not yet any data on the long-term efficiency of treatment with these cells. It seems likely that these cells could serve as real alternatives in insulin-dependent diabetes mellitus type II. Given that these cells can be generated from the recipients own resources and durable tolerance to beta cells could be induced in type I diabetic patients, there would no longer be any need for immunosuppression. The first clinical trials have been conducted successfully, and MSCs seem to be the current cell candidate of choice, but more in vitro and in vivo research is needed to fully understand the underlying mechanisms and to estimate the efficacy and safety of these treatment options. In the authors’ opinion, the cell-based therapy approach is worth investigating and would lead not only to novel therapies but also to new insights into cell differentiation, beta-cell development, and the immune system’s role in the development of diabetes and beta-cell replacement therapies. Acknowledgement The authors would like to thank Katherine Hughes for language editing.
References 1. World Health Organization. The Global Burden of Disease: 2004 Update. WHO, Geneva, Switzerland, 2008. 2. WILD S, ROGLIC G, GREEN A et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004: 27: 1047. 3. GRUESSNER AC, SUTHERLAND DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005: 19: 433. 4. MCCALL M, JAMES SHAPIRO AM. Update on Islet Transplantation. Cold Spring Harb Perspect Med 2012: 2: a007823. 5. TRUONG W, LAKEY JR, RYAN EA et al. Clinical islet transplantation at the University of Alberta – the Edmonton experience. Clin Transpl 2005: 153.
Alternatives to islet transplantation 6. SHAPIRO AM. State of the art of clinical islet transplantation and novel protocols of immunosuppression. Curr Diab Rep 2011: 11: 345. 7. ASSADY S, MAOR G, AMIT M et al. Insulin production by human embryonic stem cells. Diabetes 2001: 50: 1691. 8. ALIPIO Z, LIAO W, ROEMER EJ et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci USA 2010: 107: 13426. 9. PHADNIS SM, JOGLEKAR MV, DALVI MP et al. Human bone marrow-derived mesenchymal cells differentiate and mature into endocrine pancreatic lineage in vivo. Cytotherapy 2011: 13: 279. 10. YANG L, LI S, HATCH H et al. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci USA 2002: 99: 8078. 11. YAMANAKA S. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 2012: 10: 678. 12. JEON K, LIM H, KIM JH et al. Differentiation and transplantation of functional pancreatic beta cells generated from induced pluripotent stem cells derived from a type 1 diabetes mouse model. Stem Cells Dev 2012: 21: 2642. 13. CAPLAN AI. Mesenchymal stem cells. J Orthop Res 1991: 9: 641. 14. PITTENGER MF, MACKAY AM, BECK SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999: 284: 143. 15. LANGE C, BASSLER P, LIOZNOV MV et al. Hepatocytic gene expression in cultured rat mesenchymal stem cells. Transplant Proc 2005: 37: 276. 16. LANGE C, BASSLER P, LIOZNOV MV et al. Liver-specific gene expression in mesenchymal stem cells is induced by liver cells. World J Gastroenterol 2005: 11: 4497.
17. LANGE C, BRUNS H, KLUTH D et al. Hepatocytic differentiation of mesenchymal stem cells in cocultures with fetal liver cells. World J Gastroenterol 2006: 12: 2394. 18. VANIKAR AV, DAVE SD, THAKKAR UG et al. Cotransplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: a novel therapy for insulin-dependent diabetes mellitus. Stem Cells Int 2010: 2010: 582382. 19. JIANG R, HAN Z, ZHUO G et al. Transplantation of placenta-derived mesenchymal stem cells in type 2 diabetes: a pilot study. Front Med 2011: 5: 94. 20. GROMPE M. Pancreatic-hepatic switches in vivo. Mech Dev 2003: 120: 99. 21. ZARET KS, GROMPE M. Generation and regeneration of cells of the liver and pancreas. Science 2008: 322: 1490. 22. REDDY JK, RAO MS, YELDANDI AV et al. Pancreatic hepatocytes. An in vivo model for cell lineage in pancreas of adult rat. Dig Dis Sci 1991: 36: 502. 23. KIM S, SHIN J, KIM H et al. Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration. Lab Invest 2007: 87: 702. 24. BIRD TG, LORENZINI S, FORBES SJ. Activation of stem cells in hepatic diseases. Cell Tissue Res 2008: 331: 283. 25. SCHMELZER E, REID LM. EpCAM expression in normal, non-pathological tissues. Front Biosci 2008: 13: 3096. 26. FIEGEL HC, PARK JJ, LIOZNOV MV et al. Characterization of cell types during rat liver development. Hepatology 2003: 37: 148. 27. ZVIBEL I, MIRI B, EINAV H et al. Isolation, characterization and culture of Thy1-positive cells from fetal rat livers. World J Gastroenterol 2006: 12: 3841. € C et al. Cell growth and dif28. FIEGEL HC, BRUNS H, HOPER ferentiation of different hepatic cells isolated from fetal rat liver in vitro. Tissue Eng 2006: 12: 123.
33
