From stem cells to beta cells possible cure for diabetes mellitus
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From Stem Cells to Beta Cells: Possible Cure for Diabetes Mellitus. By Ryan Scavinski. Diabetes Mellitus. Type 1 Diabetes is caused by the autoimmune destruction of β -cells within the pancreas. No β -cells, no insulin Diabetics need to monitor blood glucose and control it with insulin.

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From Stem Cells to Beta Cells: Possible Cure for Diabetes Mellitus

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From stem cells to beta cells possible cure for diabetes mellitus

From Stem Cells to Beta Cells: Possible Cure for Diabetes Mellitus

By Ryan Scavinski


Diabetes mellitus

Diabetes Mellitus

  • Type 1 Diabetes is caused by the autoimmune destruction of β-cells within the pancreas.

  • No β-cells, no insulin

  • Diabetics need to monitor blood glucose and control it with insulin.


Past treatments

Past Treatments

  • Transplantation of pancreatic islet cells

  • Problems

    • Patient requires more than 600 islets/kg body weight = two deceased organ donors

    • Immunological rejection


Using stem cells

Using Stem Cells

  • Two approaches used to differentiate Embryonic Stem Cells into β-cells or Insulin Producing Cells (IPCs)

    • Embryoid Body Formation

    • Definitive Endoderm Formation


Embryoid body formation

Embryoid Body Formation

  • An embryoid is the arrangement of stem cells destined to differentiate into the ectoderm, mesoderm and endoderm.

  • With multiple treatment of growth factors, Embryonic stem cells give rise to Nestin cells, which in turn differentiate into IPCs.


Problems

Problems

  • Low efficiency for producing IPCs

  • Also showed development of tumors in the kidney and spleen in some transplanted mice.


Definitive endoderm approach

Definitive Endoderm Approach

  • This approach bypasses the Embryoid formation and generates the endoderm, in which produce the cells needed for insulin production.


Differentiation steps

Differentiation Steps

  • 1. ESCs were placed onto a culture dish with a chemically defined medium (CDM) containing 50 ng/mL Activin A for 4 days


From stem cells to beta cells possible cure for diabetes mellitus

  • With and without Activin A

  • PCR of expression of endoderm genes

    • Gapd, sox17, pdx1, hlxb9, hnf4a and insulin

gapd sox17 pdx1 hlxb9 hnf4α insulin


Continued

continued

  • 2. Then the cells were transferred onto a CDM with 10-6 M Retinoic acid (RA) for another 4 days


From stem cells to beta cells possible cure for diabetes mellitus

Without Activin A and RA

With Activin A and RA

small clusters of differentiated ES


From stem cells to beta cells possible cure for diabetes mellitus

PCR

  • A+/RA+

  • A-/RA-

  • A+/RA-

  • A-/RA+

gapd sox17 pdx1 hlxb9 hnf4α insulin


Continued1

continued

  • 3. Then the CDM was changed to modified islet maturation medium containing bFGF- a pancreatic cell maturation factor for 3 days

  • 4. Finally the differentiated cells were switched to a islet maturation medium containing nicotinamide and the bFGF for another 3 days.


From stem cells to beta cells possible cure for diabetes mellitus

  • In this final stage, many differentiated cells formed spherical clusters

  • Also expressed the pancreatic β cell markers such as pdx1, INSULIN, glucokinase and glut2 shown in PCR


Differentiated embryonic stem cells

Differentiated Embryonic Stem Cells

gapd sox17 pdx1 hlxb9 hnf4α insulin glut2 Amy SST Sur1 GCG GCK

Maturation

Control


From stem cells to beta cells possible cure for diabetes mellitus

  • To test cells for insulin release, cells were incubated in buffer containing 2.5 mM glucose for 15 min

  • Then incubated with 27.5 mM glucose for another 15 min

  • Tested for insulin release with a Rat/Mouse insulin ELISA


From stem cells to beta cells possible cure for diabetes mellitus

2.5 mM

27.5 mM

Insulin secretion (ng/mg)

Suspension Adhesion


Transplantation

Transplantation

  • Differentiated cells were transplanted under the renal capsule (kidney) of diabetic mice.

  • 30% showed normal blood glucose levels for 6 weeks

  • They removed the cell transplanted kidney-mice regained hyperglycemia


From stem cells to beta cells possible cure for diabetes mellitus

30

25

20

15

10

5

0

Blood glucose (mM)

0 7 14 21 28 35 42 49 56

Days after transplantation


Results and discussion

Results and Discussion

  • The combination of Activin A and Retinoic Acid is an effective method to induce Embryonic Stem Cells to differentiate into insulin producing cells

  • Further research in needed to see if the difference between human and mouse will impair the function of transplanted ESC derived cells


My opinion

My Opinion


From stem cells to beta cells possible cure for diabetes mellitus

  • Reference:

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

  • Raikwar, S. and Zavazava, N. 2009. Insulin producing cells derived from embryonic stem cells: are we there yet?. Journal of Cellular Physiology, 218 256-263

  • Jiang, W., Shi, Y., Zhao, D., Chen, S., Youg, J., Zhang, J., Qing, T., Sun, X., Zhang, P., Ding, M., Li, D., and Deng, H. 2007. In vitro derivation of functional insulin producing cells from human embryonic stem cells. Cell Research. 17 333-344


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