Skip to main content
SpringerLink
Log in

Regenerative Medicine for Diabetes Treatment: New β-Cell Sources

  • Chapter
  • First Online:
Stem Cell Genetics for Biomedical Research

  • 783 Accesses

Abstract

Diabetes results from an insufficient number of functional insulin-producing pancreatic β cells. Hence, the replenishment of the β cell population, either by induction of endogenous regeneration or by replacement with substitute β cells generated ex vivo, has long been viewed as a promising strategy to definitely cure this disease.One main topic of debate in the field has been the existence of facultative or dedicated progenitors that can give rise to new insulin-producing cells. On the other hand, recent major advances in in vitro directed differentiation protocols have put embryonic and induced pluripotent stem cells on the spotlight as promising cell sources of transplantable β cells. In this chapter, we will discuss current knowledge and future perspectives on both of theseapproaches. The identity of the optimal candidate cell source for β cell replenishment in diabetic patients remains an open and exciting question that will need to be addressed in future investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 119.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Afelik S, Jensen J (2013) Notch signaling in the pancreas: patterning and cell fate specification. Wiley Interdiscip Rev Dev Biol 2(4):531–544

    Article  PubMed  CAS  Google Scholar 

  2. Afelik S, Qu X, Hasrouni E, Bukys MA, Deering T, Nieuwoudt S, Rogers W, Macdonald RJ, Jensen J (2012) Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells. Development 139(10):1744–1753

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Afelik S, Rovira M (2017a) Pancreatic β-cell regeneration: advances in understanding the genes and signaling pathways involved. Genome Med 9(1):42

    Article  PubMed  PubMed Central  Google Scholar 

  4. Afelik S, Rovira M (2017b) Pancreatic β-cell regeneration: facultative or dedicated progenitors? Mol Cell Endocrinol 445:85–94

    Article  PubMed  CAS  Google Scholar 

  5. Al-Hasani K, Pfeifer A, Courtney M, Ben-Othman N, Gjernes E, Vieira A, Druelle N, Avolio F, Ravassard P, Leuckx G, Lacas-Gervais S, Ambrosetti D, Benizri E, Hecksher-Sorensen J, Gounon P, Ferrer J, Gradwohl G, Heimberg H, Mansouri A, Collombat P (2013) Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes. Dev Cell 26(1):86–100

    Article  PubMed  CAS  Google Scholar 

  6. Arnes L, Hill JT, Gross S, Magnuson MA, Sussel L (2012) Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population. PLoS One 7(12):e52026

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Babos K, Ichida JK (2015) Small molecules take a big step by converting fibroblasts into neurons. Cell Stem Cell 17(2):127–129

    Article  PubMed  CAS  Google Scholar 

  8. Bader E, Migliorini A, Gegg M, Moruzzi N, Gerdes J, Roscioni SS, Bakhti M, Brandl E, Irmler M, Beckers J, Aichler M, Feuchtinger A, Leitzinger C, Zischka H, Wang-Sattler R, Jastroch M, Tschöp M, Machicao F, Staiger H, Häring HU, Chmelova H, Chouinard JA, Oskolkov N, Korsgren O, Speier S, Lickert H (2016) Identification of proliferative and mature β-cells in the islets of Langerhans. Nature 535(7612):430–434

    Article  PubMed  CAS  Google Scholar 

  9. Baeyens L, Lemper M, Leuckx G, De Groef S, Bonfanti P, Stangé G, Shemer R, Nord C, Scheel DW, Pan FC, Ahlgren U, Gu G, Stoffers DA, Dor Y, Ferrer J, Gradwohl G, Wright CV, Van de Casteele M, German MS, Bouwens L, Heimberg H (2014) Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice. Nat Biotechnol 32(1):76–83

    Article  PubMed  CAS  Google Scholar 

  10. Baron M, Veres A, Wolock SL, Faust AL, Gaujoux R, Vetere A, Ryu JH, Wagner BK, Shen-Orr SS, Klein AM, Melton DA, Yanai I (2016) A single-cell transcriptomic map of the human and mouse pancreas reveals inter- and intra-cell population structure. Cell Syst 3(4):346–360.e4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Ben-Othman N, Vieira A, Courtney M, Record F, Gjernes E, Avolio F, Hadzic B, Druelle N, Napolitano T, Navarro-Sanz S, Silvano S, Al-Hasani K, Pfeifer A, Lacas-Gervais S, Leuckx G, Marroquí L, Thévenet J, Madsen OD, Eizirik DL, Heimberg H, Kerr-Conte J, Pattou F, Mansouri A, Collombat P (2017) Long-term GABA sdministration induces alpha cell-mediated beta-like cell neogenesis. Cell 168(1–2):73–85.e11

    Article  PubMed  CAS  Google Scholar 

  12. Benitez CM, Goodyer WR, Kim SK (2012) Deconstructing pancreas developmental biology. Cold Spring Harb Perspect Biol 4(6)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Bensley RR (1911) Studies on the pancreas of the guinea pig. Am J Anat 12:297–388

    Article  Google Scholar 

  14. Benthuysen JR, Carrano AC, Sander M (2016) Advances in β cell replacement and regeneration strategies for treating diabetes. J Clin Invest 126(10):3651–3660

    Article  PubMed  PubMed Central  Google Scholar 

  15. Binot AC, Manfroid I, Flasse L, Winandy M, Motte P, Martial JA, Peers B, Voz ML (2010) Nkx6.1 and nkx6.2 regulate alpha- and beta-cell formation in zebrafish by acting on pancreatic endocrine progenitor cells. Dev Biol 340(2):397–407

    Article  PubMed  CAS  Google Scholar 

  16. Bonner-Weir S (2000) Islet growth and development in the adult. J Mol Endocrinol 24(3):297–302

    Article  PubMed  CAS  Google Scholar 

  17. Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE (1993) A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 42(12):1715–1720

    Article  PubMed  CAS  Google Scholar 

  18. Bonner-Weir S, Guo L, Li WC, Ouziel-Yahalom L, Lysy PA, Weir GC, Sharma A (2012) Islet neogenesis: a possible pathway for beta-cell replenishment. Rev Diabet Stud 9(4):407–416

    Article  PubMed  Google Scholar 

  19. Bruin JE, Asadi A, Fox JK, Erener S, Rezania A, Kieffer TJ (2015a) Accelerated maturation of human stem cell-derived pancreatic progenitor cells into insulin-secreting cells in Immunodeficient rats relative to mice. Stem Cell Reports 5(6):1081–1096

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Bruin JE, Rezania A, Kieffer TJ (2015b) Replacing and safeguarding pancreatic beta cells for diabetes. Sci Transl Med 7(316):316ps23

    Article  PubMed  CAS  Google Scholar 

  21. Bruin JE, Rezania A, Xu J, Narayan K, Fox JK, O'Neil JJ, Kieffer TJ (2013) Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia 56(9):1987–1998

    Article  PubMed  Google Scholar 

  22. Cavelti-Weder C, Li W, Zumsteg A, Stemann-Andersen M, Zhang Y, Yamada T, Wang M, Lu J, Jermendy A, Bee YM, Bonner-Weir S, Weir GC, Zhou Q (2016) Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice. Diabetologia 59(3):522–532

    Article  PubMed  CAS  Google Scholar 

  23. Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, Furuyama K, Thorel F, Gribble FM, Reimann F, Herrera PL (2014) Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Nature 514(7523):503–507

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Collombat P, Mansouri A (2009) Pax4 transdifferentiates glucagon-secreting alpha cells to insulin-secreting beta endocrine pancreatic cells. Med Sci (Paris) 25(8–9):763–765

    Article  Google Scholar 

  25. Collombat P, Xu X, Ravassard P, Sosa-Pineda B, Dussaud S, Billestrup N, Madsen OD, Serup P, Heimberg H, Mansouri A (2009) The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into alpha and subsequently beta cells. Cell 138(3):449–462

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Courtney M, Gjernes E, Druelle N, Ravaud C, Vieira A, Ben-Othman N, Pfeifer A, Avolio F, Leuckx G, Lacas-Gervais S, Burel-Vandenbos F, Ambrosetti D, Hecksher-Sorensen J, Ravassard P, Heimberg H, Mansouri A, Collombat P (2013) The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells. PLoS Genet 9(10):e1003934

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Courtney M, Pfeifer A, Al-Hasani K, Gjernes E, Vieira A, Ben-Othman N, Collombat P (2011) In vivo conversion of adult α-cells into β-like cells: a new research avenue in the context of type 1 diabetes. Diabetes Obes Metab 13(Suppl 1):47–52

    Article  PubMed  CAS  Google Scholar 

  28. Criscimanna A, Speicher JA, Houshmand G, Shiota C, Prasadan K, Ji B, Logsdon CD, Gittes GK, Esni F (2011) Duct cells contribute to regeneration of endocrine and acinar cells following pancreatic damage in adult mice. Gastroenterology 141(4):1451–1462, 1462.e1–6

    Article  PubMed  CAS  Google Scholar 

  29. Cusi K (2016) Treatment of patients with type 2 diabetes and non-alcoholic fatty liver disease: current approaches and future directions. Diabetologia 59:1112

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. D'Amour KA, Agulnick AD, Eliazer S, Kelly OG, Kroon E, Baetge EE (2005) Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 23(12):1534–1541

    Article  PubMed  CAS  Google Scholar 

  31. D'Amour KA, Bang AG, Eliazer S, Kelly OG, Agulnick AD, Smart NG, Moorman MA, Kroon E, Carpenter MK, Baetge EE (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat Biotechnol 24(11):1392–1401

    Article  PubMed  CAS  Google Scholar 

  32. Delaspre F, Beer RL, Rovira M, Huang W, Wang G, Gee S, Vitery M e C, Wheelan SJ, Parsons MJ (2015) Centroacinar cells are progenitors that contribute to endocrine pancreas regeneration. Diabetes 64(10):3499–3509

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Desai BM, Oliver-Krasinski J, De Leon DD, Farzad C, Hong N, Leach SD, Stoffers DA (2007) Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration. J Clin Invest 117(4):971–977

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Desai T, Shea LD (2017) Advances in islet encapsulation technologies. Nat Rev Drug Discov 16(5):338–350

    Article  PubMed  CAS  Google Scholar 

  35. Dor Y, Brown J, Martinez OI, Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429(6987):41–46

    Article  PubMed  CAS  Google Scholar 

  36. Dorrell C, Schug J, Canaday PS, Russ HA, Tarlow BD, Grompe MT, Horton T, Hebrok M, Streeter PR, Kaestner KH, Grompe M (2016) Human islets contain four distinct subtypes of β cells. Nat Commun 7:11756

    Article  PubMed  PubMed Central  Google Scholar 

  37. El-Gohary Y, Tulachan S, Branca M, Sims-Lucas S, Guo P, Prasadan K, Shiota C, Gittes GK (2012) Whole-mount imaging demonstrates hypervascularity of the pancreatic ducts and other pancreatic structures. Anat Rec (Hoboken) 295(3):465–473

    Article  Google Scholar 

  38. El-Gohary Y, Wiersch J, Tulachan S, Xiao X, Guo P, Rymer C, Fischbach S, Prasadan K, Shiota C, Gaffar I, Song Z, Galambos C, Esni F, Gittes GK (2016) Intraislet pancreatic ducts can give rise to insulin-positive cells. Endocrinology 157(1):166–175

    Article  PubMed  CAS  Google Scholar 

  39. Fujitani Y, Fujitani S, Boyer DF, Gannon M, Kawaguchi Y, Ray M, Shiota M, Stein RW, Magnuson MA, Wright CV (2006) Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation. Genes Dev 20(2):253–266

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Fukuda A, Kawaguchi Y, Furuyama K, Kodama S, Horiguchi M, Kuhara T, Kawaguchi M, Terao M, Doi R, Wright CV, Hoshino M, Chiba T, Uemoto S (2008) Reduction of Ptf1a gene dosage causes pancreatic hypoplasia and diabetes in mice. Diabetes 57(9):2421–2431

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, Hosokawa S, Elbahrawy A, Soeda T, Koizumi M, Masui T, Kawaguchi M, Takaori K, Doi R, Nishi E, Kakinoki R, Deng JM, Behringer RR, Nakamura T, Uemoto S (2011) Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43(1):34–41

    Article  PubMed  CAS  Google Scholar 

  42. Ghaye AP, Bergemann D, Tarifeño-Saldivia E, Flasse LC, Von Berg V, Peers B, Voz ML, Manfroid I (2015) Progenitor potential of nkx6.1-expressing cells throughout zebrafish life and during beta cell regeneration. BMC Biol 13(1):70

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Gittes GK (2009) Developmental biology of the pancreas: a comprehensive review. Dev Biol 326(1):4–35

    Article  PubMed  CAS  Google Scholar 

  44. Gu D, Arnush M, Sawyer SP, Sarvetnick N (1995) Transgenic mice expressing IFN-gamma in pancreatic beta-cells are resistant to streptozotocin-induced diabetes. Am J Phys 269(6 Pt 1):E1089–E1094

    CAS  Google Scholar 

  45. Gu D, Sarvetnick N (1993) Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development 118(1):33–46

    PubMed  CAS  Google Scholar 

  46. Haegebarth A, Clevers H (2009) Wnt signaling, lgr5, and stem cells in the intestine and skin. Am J Pathol 174(3):715–721

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Heimberg H, De Vos A, Vandercammen A, Van Schaftingen E, Pipeleers D, Schuit F (1993) Heterogeneity in glucose sensitivity among pancreatic beta-cells is correlated to differences in glucose phosphorylation rather than glucose transport. EMBO J 12(7):2873–2879

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Hrvatin S, O'Donnell CW, Deng F, Millman JR, Pagliuca FW, DiIorio P, Rezania A, Gifford DK, Melton DA (2014) Differentiated human stem cells resemble fetal, not adult, beta cells. Proc Natl Acad Sci U S A 111(8):3038–3043

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Inada A, Nienaber C, Katsuta H, Fujitani Y, Levine J, Morita R, Sharma A, Bonner-Weir S (2008) Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci U S A 105(50):19915–19919

    Article  PubMed  PubMed Central  Google Scholar 

  50. International Diabetes Federation (2015) IDF Diabetes, 7 ed. Brussels, Belgium

    Google Scholar 

  51. Johnson JD (2016) The quest to make fully functional human pancreatic beta cells from embryonic stem cells: climbing a mountain in the clouds. Diabetologia 59(10):2047–2057

    Article  PubMed  CAS  Google Scholar 

  52. Jones DL, Wagers AJ (2008) No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol 9(1):11–21

    Article  PubMed  CAS  Google Scholar 

  53. Kelly OG, Chan MY, Martinson LA, Kadoya K, Ostertag TM, Ross KG, Richardson M, Carpenter MK, D'Amour KA, Kroon E, Moorman M, Baetge EE, Bang AG (2011) Cell-surface markers for the isolation of pancreatic cell types derived from human embryonic stem cells. Nat Biotechnol 29(8):750–756

    Article  PubMed  CAS  Google Scholar 

  54. Klochendler A, Caspi I, Corem N, Moran M, Friedlich O, Elgavish S, Nevo Y, Helman A, Glaser B, Eden A, Itzkovitz S, Dor Y (2016) The genetic program of pancreatic beta-cell replication in vivo. Diabetes 65(7):2081–2093

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Kopinke D, Brailsford M, Shea JE, Leavitt R, Scaife CL, Murtaugh LC (2011) Lineage tracing reveals the dynamic contribution of Hes1+ cells to the developing and adult pancreas. Development 138(3):431–441

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Kopinke D, Murtaugh LC (2010) Exocrine-to-endocrine differentiation is detectable only prior to birth in the uninjured mouse pancreas. BMC Dev Biol 10:38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Kopp JL, Dubois CL, Hao E, Thorel F, Herrera PL, Sander M (2011a) Progenitor cell domains in the developing and adult pancreas. Cell Cycle 10(12):1921–1927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kopp JL, Dubois CL, Schaffer AE, Hao E, Shih HP, Seymour PA, Ma J, Sander M (2011b) Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138(4):653–665

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Kroon E, Martinson LA, Kadoya K, Bang AG, Kelly OG, Eliazer S, Young H, Richardson M, Smart NG, Cunningham J, Agulnick AD, D'Amour KA, Carpenter MK, Baetge EE (2008) Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 26(4):443–452

    Article  PubMed  CAS  Google Scholar 

  60. Kushner JA, Weir GC, Bonner-Weir S (2010) Ductal origin hypothesis of pancreatic regeneration under attack. Cell Metab 11(1):2–3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Lee MG, Ohana E, Park HW, Yang D, Muallem S (2012) Molecular mechanism of pancreatic and salivary gland fluid and HCO3 secretion. Physiol Rev 92(1):39–74

    Article  PubMed  CAS  Google Scholar 

  62. Li J, Casteels T, Frogne T, Ingvorsen C, Honoré C, Courtney M, Huber KV, Schmitner N, Kimmel RA, Romanov RA, Sturtzel C, Lardeau CH, Klughammer J, Farlik M, Sdelci S, Vieira A, Avolio F, Briand F, Baburin I, Májek P, Pauler FM, Penz T, Stukalov A, Gridling M, Parapatics K, Barbieux C, Berishvili E, Spittler A, Colinge J, Bennett KL, Hering S, Sulpice T, Bock C, Distel M, Harkany T, Meyer D, Superti-Furga G, Collombat P, Hecksher-Sørensen J, Kubicek S (2017) Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity. Cell 168(1–2):86–100.e15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Li K, Zhu S, Russ HA, Xu S, Xu T, Zhang Y, Ma T, Hebrok M, Ding S (2014a) Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages. Cell Stem Cell 14(2):228–236

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Li W, Cavelti-Weder C, Zhang Y, Clement K, Donovan S, Gonzalez G, Zhu J, Stemann M, Xu K, Hashimoto T, Yamada T, Nakanishi M, Zeng S, Gifford D, Meissner A, Weir G, Zhou Q (2014b) Long-term persistence and development of induced pancreatic beta cells generated by lineage conversion of acinar cells. Nat Biotechnol 32(12):1223–1230

    Article  PubMed  CAS  Google Scholar 

  65. Li W, Ding S (2010) Generation of novel rat and human pluripotent stem cells by reprogramming and chemical approaches. Methods Mol Biol 636:293–300

    Article  PubMed  CAS  Google Scholar 

  66. Li W, Nakanishi M, Zumsteg A, Shear M, Wright C, Melton DA, Zhou Q (2014c) In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes. elife 3:e01846

    Article  PubMed  PubMed Central  Google Scholar 

  67. Li W, Wei W, Zhu S, Zhu J, Shi Y, Lin T, Hao E, Hayek A, Deng H, Ding S (2009) Generation of rat and human induced pluripotent stem cells by combining genetic reprogramming and chemical inhibitors. Cell Stem Cell 4(1):16–19

    Article  PubMed  CAS  Google Scholar 

  68. Li WC, Rukstalis JM, Nishimura W, Tchipashvili V, Habener JF, Sharma A, Bonner-Weir S (2010) Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats. J Cell Sci 123(Pt 16):2792–2802

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Lingohr MK, Buettner R, Rhodes CJ (2002) Pancreatic beta-cell growth and survival--a role in obesity-linked type 2 diabetes? Trends Mol Med 8(8):375–384

    Article  PubMed  CAS  Google Scholar 

  70. Meier JJ, Butler AE, Saisho Y, Monchamp T, Galasso R, Bhushan A, Rizza RA, Butler PC (2008) Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 57(6):1584–1594

    Article  PubMed  CAS  Google Scholar 

  71. Menge BA, Breuer TG, Ritter PR, Uhl W, Schmidt WE, Meier JJ (2012) Long-term recovery of β-cell function after partial pancreatectomy in humans. Metabolism 61(5):620–624

    Article  PubMed  CAS  Google Scholar 

  72. Millman JR, Xie C, Van Dervort A, Gurtler M, Pagliuca FW, Melton DA (2016) Generation of stem cell-derived beta-cells from patients with type 1 diabetes. Nat Commun 7:11463

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Muraro, M. J., Dharmadhikari, G., Grün, D., Groen, N., Dielen, T., Jansen, E., van Gurp, L., Engelse, M. A., Carlotti, F., de Koning, E. J. and van Oudenaarden, A. (2016) 'A single-cell transcriptome atlas of the human pancreas', Cell Syst 3(4):385-394.e3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Nir T, Melton DA, Dor Y (2007) Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 117(9):2553–2561

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Oliver-Krasinski JM, Stoffers DA (2008) On the origin of the beta cell. Genes Dev 22(15):1998–2021

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Otonkoski T, Beattie GM, Lopez AD, Hayek A (1994) Use of hepatocyte growth factor/scatter factor to increase transplantable human fetal islet cell mass. Transplant Proc 26(6):3334

    PubMed  CAS  Google Scholar 

  77. Pagliuca FW, Millman JR, Gurtler M, Segel M, Van Dervort A, Ryu JH, Peterson QP, Greiner D, Melton DA (2014) Generation of functional human pancreatic beta cells in vitro. Cell 159(2):428–439

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Pan FC, Bankaitis ED, Boyer D, Xu X, Van de Casteele M, Magnuson MA, Heimberg H, Wright CV (2013) Spatiotemporal patterns of multipotentiality in Ptf1a-expressing cells during pancreas organogenesis and injury-induced facultative restoration. Development 140(4):751–764

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Papizan JB, Singer RA, Tschen SI, Dhawan S, Friel JM, Hipkens SB, Magnuson MA, Bhushan A, Sussel L (2011) Nkx2.2 repressor complex regulates islet beta-cell specification and prevents beta-to-alpha-cell reprogramming. Genes Dev 25(21):2291–2305

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Phillips JM, O'Reilly L, Bland C, Foulis AK, Cooke A (2007) Patients with chronic pancreatitis have islet progenitor cells in their ducts, but reversal of overt diabetes in NOD mice by anti-CD3 shows no evidence for islet regeneration. Diabetes 56(3):634–640

    Article  PubMed  CAS  Google Scholar 

  81. Puri S, Folias AE, Hebrok M (2015) Plasticity and dedifferentiation within the pancreas: development, homeostasis, and disease. Cell Stem Cell 16(1):18–31

    Article  PubMed  CAS  Google Scholar 

  82. Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O'Dwyer S, Quiskamp N, Mojibian M, Albrecht T, Yang YH, Johnson JD, Kieffer TJ (2014) Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32(11):1121–1133

    Article  PubMed  CAS  Google Scholar 

  83. Rezania A, Bruin JE, Xu J, Narayan K, Fox JK, O'Neil JJ, Kieffer TJ (2013) Enrichment of human embryonic stem cell-derived NKX6.1-expressing pancreatic progenitor cells accelerates the maturation of insulin-secreting cells in vivo. Stem Cells 31(11):2432–2442

    Article  PubMed  CAS  Google Scholar 

  84. Rezania A, Riedel MJ, Wideman RD, Karanu F, Ao Z, Warnock GL, Kieffer TJ (2011) Production of functional glucagon-secreting alpha-cells from human embryonic stem cells. Diabetes 60(1):239–247

    Article  PubMed  CAS  Google Scholar 

  85. Rieck S, Bankaitis ED, Wright CV (2012) Lineage determinants in early endocrine development. Semin Cell Dev Biol 23(6):673–684

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Rooman I, Bouwens L (2004) Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57Bl6/J mice treated with alloxan. Diabetologia 47(2):259–265

    Article  PubMed  CAS  Google Scholar 

  87. Rosenberg L (1995) In vivo cell transformation: neogenesis of beta cells from pancreatic ductal cells. Cell Transplant 4(4):371–383

    PubMed  CAS  Google Scholar 

  88. Rovira M, Scott SG, Liss AS, Jensen J, Thayer SP, Leach SD (2010) Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc Natl Acad Sci U S A 107(1):75–80

    Article  PubMed  CAS  Google Scholar 

  89. Russ HA, Parent AV, Ringler JJ, Hennings TG, Nair GG, Shveygert M, Guo T, Puri S, Haataja L, Cirulli V, Blelloch R, Szot GL, Arvan P, Hebrok M (2015) Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J 34(13):1759–1772

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Salomon D, Meda P (1986) Heterogeneity and contact-dependent regulation of hormone secretion by individual B cells. Exp Cell Res 162(2):507–520

    Article  PubMed  CAS  Google Scholar 

  91. Sancho R, Gruber R, Gu G, Behrens A (2014) Loss of Fbw7 reprograms adult pancreatic ductal cells into alpha, delta, and beta cells. Cell Stem Cell 15(2):139–153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Sander M, Sussel L, Conners J, Scheel D, Kalamaras J, Dela Cruz F, Schwitzgebel V, Hayes-Jordan A, German M (2000) Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas. Development 127(24):5533–5540

    PubMed  CAS  Google Scholar 

  93. Sato T, Clevers H (2015) SnapShot: growing organoids from stem cells. Cell 161(7):1700–1700.e1

    Article  PubMed  CAS  Google Scholar 

  94. Schaffer AE, Taylor BL, Benthuysen JR, Liu J, Thorel F, Yuan W, Jiao Y, Kaestner KH, Herrera PL, Magnuson MA, May CL, Sander M (2013) Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet 9(1):e1003274

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Schofield PK, Treherne JE (1978) Kinetics of sodium and lithium movements across the blood-brain barrier of an insect. J Exp Biol 74:239–251

    PubMed  CAS  Google Scholar 

  96. Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, Gloyn AL, Edghill EL, Hattersley AT, Wellauer PK, Goodwin G, Houlston RS (2004) Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 36(12):1301–1305

    Article  PubMed  CAS  Google Scholar 

  97. Seymour PA (2014) Sox9: a master regulator of the pancreatic program. Rev Diabet Stud 11(1):51–83

    Article  PubMed  PubMed Central  Google Scholar 

  98. Shirakawa J, Kulkarni RN (2016) Novel factors modulating human beta-cell proliferation. Diabetes Obes Metab 18 Suppl 1:71–77

    Article  PubMed  CAS  Google Scholar 

  99. Solar M, Cardalda C, Houbracken I, Martín M, Maestro MA, De Medts N, Xu X, Grau V, Heimberg H, Bouwens L, Ferrer J (2009) Pancreatic exocrine duct cells give rise to insulin-producing beta cells during embryogenesis but not after birth. Dev Cell 17(6):849–860

    Article  PubMed  CAS  Google Scholar 

  100. Sussel L, Kalamaras J, Hartigan-O'Connor DJ, Meneses JJ, Pedersen RA, Rubenstein JL, German MS (1998) Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells. Development 125(12):2213–2221

    PubMed  CAS  Google Scholar 

  101. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131(5):861–872

    Article  PubMed  CAS  Google Scholar 

  102. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676

    Article  PubMed  CAS  Google Scholar 

  103. Tanaka EM, Reddien PW (2011) The cellular basis for animal regeneration. Dev Cell 21(1):172–185

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Teta M, Rankin MM, Long SY, Stein GM, Kushner JA (2007) Growth and regeneration of adult beta cells does not involve specialized progenitors. Dev Cell 12(5):817–826

    Article  PubMed  CAS  Google Scholar 

  105. Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S, Herrera PL (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464(7292):1149–1154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Tsunemoto RK, Eade KT, Blanchard JW, Baldwin KK (2015) Forward engineering neuronal diversity using direct reprogramming. EMBO J 34(11):1445–1455

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Vegas AJ, Veiseh O, Gurtler 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 (2016) Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat Med 22(3):306–311

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Vierbuchen T, Wernig M (2011) Direct lineage conversions: unnatural but useful? Nat Biotechnol 29(10):892–907

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Vierbuchen T, Wernig M (2012) Molecular roadblocks for cellular reprogramming. Mol Cell 47(6):827–838

    Article  PubMed  CAS  Google Scholar 

  110. Weaver CV, Sorenson RL, Kaung HC (1985) Immunocytochemical localization of insulin-immunoreactive cells in the pancreatic ducts of rats treated with trypsin inhibitor. Diabetologia 28(10):781–785

    PubMed  CAS  Google Scholar 

  111. Westphalen CB, Takemoto Y, Tanaka T, Macchini M, Jiang Z, Renz BW, Chen X, Ormanns S, Nagar K, Tailor Y, May R, Cho Y, Asfaha S, Worthley DL, Hayakawa Y, Urbanska AM, Quante M, Reichert M, Broyde J, Subramaniam PS, Remotti H, Su GH, Rustgi AK, Friedman RA, Honig B, Califano A, Houchen CW, Olive KP, Wang TC (2016) Dclk1 defines quiescent pancreatic progenitors that promote injury-induced regeneration and tumorigenesis. Cell Stem Cell 18(4):441–455

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Wilcox CL, Terry NA, Walp ER, Lee RA, May CL (2013) Pancreatic α-cell specific deletion of mouse Arx leads to α-cell identity loss. PLoS One 8(6):e66214

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Xu G, Stoffers DA, Habener JF, Bonner-Weir S (1999) Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48(12):2270–2276

    Article  PubMed  CAS  Google Scholar 

  114. Xu J, Du Y, Deng H (2015) Direct lineage reprogramming: strategies, mechanisms, and applications. Cell Stem Cell 16(2):119–134

    Article  PubMed  CAS  Google Scholar 

  115. Xu, X., D'Hoker, J., Stangé, G., Bonné, S., De Leu, N., Xiao, X., Van de Casteele, M., Mellitzer, G., Ling, Z., Pipeleers, D., Bouwens, L., Scharfmann, R., Gradwohl, G. and Heimberg, H. (2008) 'Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas', Cell, 132(2), pp. 197–207

    Article  PubMed  CAS  Google Scholar 

  116. Yanger K, Stanger BZ (2011) Facultative stem cells in liver and pancreas: fact and fancy. Dev Dyn 240(3):521–529

    Article  PubMed  PubMed Central  Google Scholar 

  117. Yoneda S, Uno S, Iwahashi H, Fujita Y, Yoshikawa A, Kozawa J, Okita K, Takiuchi D, Eguchi H, Nagano H, Imagawa A, Shimomura I (2013) Predominance of beta-cell neogenesis rather than replication in humans with an impaired glucose tolerance and newly diagnosed diabetes. J Clin Endocrinol Metab 98(5):2053–2061

    Article  PubMed  CAS  Google Scholar 

  118. Zhang M, Lin Q, Qi T, Wang T, Chen CC, Riggs AD, Zeng D (2016a) Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into beta cells in mice with reversal of diabetes. Proc Natl Acad Sci U S A 113(3):650–655

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Zhang M, Lin Q, Qi T, Wang T, Chen CC, Riggs AD, Zeng D (2016b) Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into β cells in mice with reversal of diabetes. Proc Natl Acad Sci U S A 113(3):650–655

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA (2008) In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature 455(7213):627–632

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  121. Zhou Q, Law AC, Rajagopal J, Anderson WJ, Gray PA, Melton DA (2007) A multipotent progenitor domain guides pancreatic organogenesis. Dev Cell 13(1):103–114

    Article  PubMed  CAS  Google Scholar 

  122. Zhu S, Russ HA, Wang X, Zhang M, Ma T, Xu T, Tang S, Hebrok M, Ding S (2016) Human pancreatic beta-like cells converted from fibroblasts. Nat Commun 7:10080

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Zhu S, Wang H, Ding S (2015) Reprogramming fibroblasts toward cardiomyocytes, neural stem cells and hepatocytes by cell activation and signaling-directed lineage conversion. Nat Protoc 10(7):959–973

    Article  PubMed  CAS  Google Scholar 

  124. Zipori D (2004) The nature of stem cells: state rather than entity. Nat Rev Genet 5(11):873–878

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain

    Rosa Gasa

  2. Diabetes and Obesity Research Laboratory, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain

    Rosa Gasa

  3. Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Barcelona, Spain

    Meritxell Rovira

Authors
  1. Rosa Gasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meritxell Rovira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meritxell Rovira .

Editor information

Editors and Affiliations

  1. Duran i Reynals Hospital, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

    Raul Delgado-Morales

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Gasa, R., Rovira, M. (2018). Regenerative Medicine for Diabetes Treatment: New β-Cell Sources. In: Delgado-Morales, R. (eds) Stem Cell Genetics for Biomedical Research. Springer, Cham. https://doi.org/10.1007/978-3-319-90695-9_9

Download citation

Publish with us

Policies and ethics

Search

Navigation