Centro Andaluz de Biología Molecular y Medicina Regenerativa

Cellullar therapy of the Diabetes Mellitus

Research areas:

-Diabetes Mellitus cell therapy.
-Embryonic Stem Cells Biology.
-Differentiation of Stem Cells toward mesoderm “myocardial therapy”.
-Directed differentiation towards ectoderm.

Diabetes Mellitus cell therapy.

Diabetes is one of the most prevalent diseases among the industrialized countries and implicates a high health care expense, not only because of the disease itself but also because of other associated complications such as retinopathies, nephropathies, neuropathies, diabetic-foot and cardiovascular problems. Pancreatic islets transplant using the Edmonton protocol represents an efficient Cell therapy. Nevertheless, this technique is limited by the lack of organs and effective immunosuppression drugs. Despite all the improvements needed for this protocol, the main obstacle to face is the existing disparity between the number of potential donors and the number of the possible receptors; so far an alternative source of cells is needed.

Stem cells have two very interesting characteristics: the self-renewal capacity under controlled culture conditions and the capacity to differentiate to any of the cell types in the organism. These cells have opened a new way to come alongside the regenerative medicine. Although the possibility to generate certain cell type from human embryonic stem cells (hESCs) is still far, research in the self-renewal processes, differentiation and selection of the insulin producing cells and other cell types derived from mouse embryonic stem cells (mESCs) had given a rise to promising results that are the basis to study these processes in human stem cells. The same proposal is widespread among other areas of research such as neurodegenerative diseases, cardiac complications, osteoarthicular disease…

It is necessary to go on with the efforts of developing and improving the strategies that will allow obtaining not only insulin producing cells, but cells that are able to release the insulin in suitable amounts and at appropriate times. The restoration of cell function is not the only priority in diabetes research; new therapeutic alternatives are also required. In any case, we are facing a series of challenges that will be achieved with basic research of quality and with the commitment of transferring the results to the clinic the soonest possible.

Embryonic Stem Cells Biology.

The embryonic stem cells are cell lines that have the peculiarity of combining self-renewal and pluripotency characteristics. These cells can be maintain in culture during indefinite periods of time while keeping its ability to differentiate towards any cell type “in vitro” and “in vivo”.

Our group is interested in understanding the molecular basis of the mESCs pluripotency. Most of our current knowledge comes from studies done on mESCs. Nowadays it is known that the main requirement to maintain these cells is the Leukemia Inhibitor Factor (LIF), the mESCs also depend on the expression of the transcription factors POU5f1 “Oct4” as well as “Nanog”. The relationship between intrinsic and extrinsic signalling from mESCs begins to be understood now and many projects of our group are focused on these theme.

On the other hand, the maintenance of the hESCs depends of the signalling trough the fibroblast growth factor (FGF) pathway that must be activated exogenously by adding human recombinant FGF (hrFGF-2). Contrary to the mESCs, it is complicated to maintain undifferentiated hESCs in chemical defined media; thus many lines of research of our group pursue the identification of the specific intrinsic and extrinsic needs of the hESC’s pluripotency and the optimization of the defined culture media for there growth and maintenance.

Differentiation of Stem Cells toward mesoderm “myocardial therapy”.

Regarding the early differentiation of the stem cells, we make good use of the spontaneous as well as the induced differentiation protocols of both embryonic and adult stem cells to study the molecular mechanisms of the differentiation towards cardiac, smooth and skeletal muscle.

 

Directed differentiation towards ectoderm.

Most of the advances in the stem cell research have been developed for replacing lost or damaged neural cells for the neurodegenerative disease. A current line of work entails the optimization of the ectodermal differentiation protocol, and the characterization of line specific cell surface markers from the undifferentiated stage towards the neural cell lineage.

Once again we are facing a new challenge that entails the use of stem cells in possible cell therapies. Basic research will bring without a doubt new progresses that will required a rigorous scientific evaluation and a wise judgement before the application of these therapeutic approaches in the clinics.

Current proyects:

RD12/0019/0028 (Entidad Financiadora: Instituto de Salud Carlos III, confinanciada con FEDER)
PI14/01015 (Entidad Financiadora: Instituto de Salud Carlos III, confinanciada con FEDER)
RA-120 (Entidad Financiadora: Ministerio de Sanidad, Servicios Sociales e Igualdad)
P10-CTS-6505 (Entidad Financiadora: Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía)
FI11/00301 (Entidad Financiadora: Instituto de Salud Carlos III)

Selected Publications:

Terapia Celular de la Diabetes Mellitus

Martín F, Andreu E, Rovira JM, Pertusa JAG, Raurell M, Ripoll C, Sanchez-Andrés JV, Montanya E, Soria B (1999) Mechanisms of glucose hypersensitivity in ß-cells from normoglycaemic partially pancreatectomized mice. Diabetes 48 (10): 1954-1961

Soria B, Roche E, Berná G, León-Quinto T, Reig JA, Martin F (2000) Insulin-secreting cells derived from embryonic stem-cells normalize glycaemia in streptozotocin-induced diabetic mice. Diabetes 49: 157 – 16

Soria B, Andreu E, Berná G, Fuentes E, Gil A, León-Quinto T, Martín F, Montanya E, Nadal A, Reig JA, Ripoll C, Roche E, Sanchez-Andrés JV, Segura J (2000) Engineering Pancreatic Islets Pflügers Archiv- Eur. J. Physiol. 440: 1-18

Soria B, Skoudy A, Martin F (2001) From stem cells to ?-cells: new strategies in cell therapy of diabetes mellitus. Diabetologia 44: 407- 415

Soria B (2001) In-vitro differentiation of pancreatic ß-cells. Differentiation 68: 205-219

Leon-Quinto T, Jones J, Skoudy A, Burcin M, Soria B (2004) In vitro directed differentiation of mouse embryonic stem cells into insulin-producing cells. Diabetologia. 47(8):1442-51

Roche E, Sepulcre P, Reig JA, Santana A, Soria B (2005) Ectodermal commitment of insulin-producing cells derived from mouse embryonic stem cells. FASEB J 19(10): 1341-1343

Runhke M, Ungefroren H. Nussler A, Martin F, Brulport M, Schorman W, Hengstler JG, Klapper W, Ulrichs K, Hutchinson JA, Soria B, Parwaresch RM, Heeckt P, Kremer B, Fandrich F (2005) Reprogramming human peripheral blood monocytes into functional hepatocyte and pancreatic islet-like cells. Gastroenterology: 128(7) : 1774 -1786

Vaca P, Martin F, Vegara JM, Rovira JM, Berná G, Soria B (2006) Induction of differentiation of ES cells into islet cells by fetal soluble factors. Stem Cells 24(2): 258- 265

Todorova MG, Soria B, Quesada I (2007) Connexin 43 and gap-junctional intercellular communication is required to maintain embryonic stem cells in a non-differentiated and proliferative state. J Cell Science. In press

Soria B, Bedoya FJ, Tejedo JR, Hmadcha A, Ruiz-Salmerón R, Lim S, Martin F. Cell therapy for diabetes mellitus: an opportunity for stem cells? Cells Tissues Organs. 2008;188(1-2):70-7. Epub 2008 Feb 29. PMID: 18305378 [PubMed – indexed for MEDLINE]

Cahuana GM, Tejedo JR, Hmadcha A, Ramírez R, Cuesta AL, Soria B, Martin F, Bedoya FJ. Nitric oxide mediates the survival action of IGF-1 and insulin in pancreatic beta cells. Cell Signal. 2008 Feb;20(2):301-10. Epub 2007 Oct 12. PMID: 18023142 [PubMed – indexed for MEDLINE]

Mecanismos Señalización Celular en Islotes Pancreáticos

Martin F, Pintor J, Rovira JM, Ripoll C, Miras-Portugal MT and Soria B (1998) Intracellular diadenosine polyphosphates: a novel second messenger in stimulus-secretion coupling. FASEB Journal 12: 1499-1506

Nadal A, Rovira JM, Laribi O, León-Quinto T, Andreu E, Ripoll C, Soria B (1998) Rapid insulinotropic effect of 17beta-oestradiol via a plasma membrane receptor. FASEB Journal. 12: 1341-1348

Nadal A, Quesada I, Soria B (1999) Homologous and heterologous unsynchronicity between identified alpha, beta and delta-cells within intact islet of Langerhans in the mouse. J. Physiol. (Lond). 517: 85- 93

Gil A, Segura J, Pertusa JAG, Soria B (2000) Monte Carlo simulation of 3-D buffered Ca2+ diffusion in neuroendocrine cells. Biophysical Journal 78: 13 – 33

Charollais A, Gjinovci A, Huarte J, Bauquis J, Nadal A, Martín F, Andreu E, Sanchez-Andrés JV, Calabrese A, Bosco D, Soria B, Wollheim CB, Herrera PL, Meda P (2000) Junctional communication of pancreatic-beta cells contributes to the control of insulin secretion and glucose tolerance. Journal of Clinical Investigation 106: 235-243

Nadal A, Ropero AB, Laribi O, Maillet M, Fuentes E, Soria B (2000) Non-genomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta. Proceedings of the National Academy of Sciences 97(21): 11603- 11608

Nadal A, Ropero AB, Fuentes E, Soria B (2001) The oestrogen plasma membrane receptor: nuclear or unclear. Trends in Pharmacological Sciences 22: 597-599

Quesada I, Rovira JM, Martín F, Roche E, Nadal A, Soria B (2002) Nuclear KATP channels trigger nuclear Ca2+ transients and gene expression. Proc. Natl. Acad. Sci. USA 99(14). 9544-9549

Quesada I, Fuentes E, Viso-León MC, Soria B, Ripoll C, Nadal A (2002) Low doses of the endocrine disruptor bisphenol-A and the native hormone 17beta estradiol rapidly activate the transcription factor CREB. FASEB J 16 (12): 1671-1673

Quesada I, Todorova MG, Soria B (2006) Different metabolic responses in alpha-, beta-, and delta-cells of the islet of Langerhans monitored by redox confocal microscopy. Biophys J 90(7): 2641-50

Quesada I, Todorova MG, Alonso-Magdalena P, Beltrá M, Carneiro EM, Martin F, Nadal A, Soria B (2006) Glucose induces opposite [Ca2+]i oscillatory patterns in identified alpha- and beta-cells within intact human islets of Langerhans. Diabetes 55(9): 2463-2469

Patents:

Inventors (signature order): Bernat Soria Escoms, Franz Martín Bermudo, Juan Antonio Reig Maciá, Genoveva Berná Amorós, Roberto Enseñat-Wasser
Títle: “Pluripotent adult stem cell from regenerative tissue”
Application Nr.: EP 01-1001-333.1
Priority Office : Europe
Extension countries: EEUU (17-4-01): USP 287105/USP 324008
Priority date: 20-01-2001
Applicant: Cardiogene.
Exploitation by: CARDION AG, Erkrath, Alemania

Inventors (signature order) : Bernat Soria Escoms, Trinidad León-Quinto, Jonathan Jones, Anouska Skoudy, FX Real
Títle : “Process for the production of cells exhibiting an islet beta-cell like state”
Application Nr. : EP 01-123-139.6
Priority Office : Europe
Extension countries :
Priority date : 27-09-2001
Applicant : CARDION AG, Erkrath, Alemania
Exploitation by : CARDION AG, Erkrath, Alemania

Inventors (signature order) : Soria Escoms, Bernat; Tejedo Huamán, Juan R.; Bedoya Bergua, Francisco Javier; Hmadcha, Abdelkrim; Mora Castilla, Sergio
Títle : “Un nuevo método para la obtención, mantenimiento y cultivo de células troncales pluripotenciales y de células progenitoras de mamífero en estado no diferenciado”
Application Nr. : P200602411
Priority Office : Spain
Extension countries :
Priority date : 19-09-2006
Applicant : Fundación Progreso y Salud, Universidad Pablo de Olavide

Senior Researchers:
  • Dr. Karim Hmadcha
Postdoctorals:
Technicians:
  • Yolanda Aguilera García
  • Nuria Mellado-Damas Sanz
Master students:
  • Maria Morales Pineda