these blog posts are written by Dr. alfredo G. Tomasselli, a Retired bio-Chemist and Bio-physicist who spent his life in Academia and The Pharmaceutical Industry researching cures and treatments for diseases such as HIV/Aids, Diabetes, and Rheumatoid arthritis. His daughter sara inspires this blog and helps to write posts. sara was diagnosed with type 1 diabetes on april 4th, 2014 at the age of 30. 

2017 Progress on reprogramming liver cells into pancreas β-like cells



This posting is for informational purposes only and in no way intended as medical and other personal advice

Summary
Procedures to produce functional human pancreatic β-like-cells from other cell types are being frequently discovered and continuously improved. The ultimate goal is to normalize the blood glucose levels of people with Type 1 Diabetes (T1D) by replacing their lost natural insulin producing β-cells with β-like-cells obtained in the laboratory. Scientists in Germany have just reported (Cerda’-Esteban et al., 2017, Reference 1) another advance towards accomplishing this goal. By studying mice embryos during their period of cell differentiation towards pancreatic and liver cell lineage, respectively, they identified a transcription factor (footnote i), referred to as TGIF2 that was able to convert liver cells to the pancreatic progenitor cells. When the latter cells were transferred to diabetic mice, they matured into cells capable of reducing blood glucose levels in these animals. Moreover, direct expression of the TGIF2 gene in the liver of diabetic mice increased their blood insulin and decreased their blood glucose. These and other accomplishments that we have already reported in our blog bring some hope that one day we will be able to replace the lost β cells of T1D people with cells made in the laboratory, and also find ways to directly convert some of their own cells into β-like cells and normalize their blood glucose.

Narrative
Type 1 Diabetes (T1D) is an autoimmune disease whereby the insulin producing pancreatic β-cells are killed or rendered dysfunctional by the immune system gone awry. There is no cure for T1D and daily insulin injections are essentially the only therapeutic option to treat it. Insulin treatment is an effective therapy if strictly matched to carbohydrate intake because it helps the majority of patients to bring their glucose levels within the normal physiological range. Yet, many T1D people are not able to consistently control their blood sugar and, in the long run, may suffer serious health consequences. Type 1 Diabetes’ seriousness and its worldwide increasing incidence along with the overwhelming emotional, physical, and economical impacts on those affected by the disease demand an immediate cure.

β-cell replacement therapy seems a promising approach to study and develop treatments for T1D and eventually find a cure for it. Many efforts are devoted to searching the best sources of cell types and the most efficient technologies to accomplish their conversion into insulin producing β-cells in the laboratory and directly in animal models. The ultimate goal is to transplant these β-cells into T1D people or, even better, to create them directly within the body of a T1D person which would thereby replace the lost or dysfunctional ones. In previous narratives we discussed successful studies for the production of pancreatic β-like cells from stem cells, stomach cells, skin cells of T1D and non-diseased people, and pancreatic α-cells (Reference 2-5); moreover, we pointed out that transplanting these cells into animal models of T1D, restored the ability of these animals to keep their glucose levels under control. 

Here we report the recent work by scientists at the Max Delbrück Center for Molecular Medicine in Berlin (Germany) and their collaborators at other academic institutions in Germany (Cerda’-Esteban et al., 2017, Reference 1) describing the conversion of liver cells into functional pancreatic β-like-cells.  

The liver and pancreas develop from the same population of embryonic cells; these cells differentiate at some point in their development and form progenitor (immature) liver and pancreas cells prior to becoming mature cells (Footnote ii). Typically, to reprogram a specific cell line into another, in this case liver cells into β-cells, scientists have to understand how genes are regulated during the differentiation process. In particular, they have to identify peculiar factors that, at the branchpoint of cell differentiation towards their cell lineage fate, promote the development of the pancreas cell lineage while inhibiting the development of the liver cell lineage. The scientists of this study (Cerda’-Esteban et al., 2017, Reference 1) took mice embryos during their period of cell differentiation towards pancreatic and liver cell lines, respectively. They isolated the two progenitor cell types and examined the expression of their genes (gene profiling). They identified a transcription factor, referred to as TGIF2 (Three-Amino-acid-Loop-Extension homeobox TG-interacting factor 2) that when expressed at a specific differentiation point commits the cells to the pancreatic lineage, while it suppresses their ability to become liver cells.

The results supported testing whether TGIF2 expression was able to reprogram liver cells to pancreas cells (ex vivo, footnote iii). They inserted the Tgif2 gene in a Lentiviral vector (LV) and transduced (footnote 3) it in a hepatic (from the liver) cell line (referred to as BAML) established from adult wild-type mouse liver. The expression of Tgif2 in BAML hepatocytes confers upon them the gene expression signature typical of pancreatic progenitor cells. They named the BALM hepatic cells expressing the Tgif2, “TGIF2-induced Pancreatic Progenitor (TiPP)” cells.

Next the scientists tested whether TiPP cells would complete their maturation process to become functional insulin producing pancreatic β-like-cells when implanted under the kidney capsule of mice (in vivo experiment) rendered diabetic by β-cell depletion. Indeed, they found that the transplanted TiPP cells improved the animals’ blood level quickly and were able to keep it stable for the 8-week duration of the experiment, at which time they also observed that no tumors were present.   

In addition, they wanted to find out whether ectopic expression (footnote iv) of Tgif2 directly into the liver of diabetic mice (in vivo experiment) would foster the conversion of these cells into pancreatic β-like-cells and improve glucose. They inserted Tgif2 gene into a recombinant viral vector and accomplished delivery exclusively to the liver cells of these animals. They observed that 4 out of the 7 diabetic mice that received the Tgif2 gene had an increased level of insulin and lowered blood glucose levels (occurred 60 days after the Tgif2 gene insertion) compared to control animals (with no Tgif2 gene delivered to their livers),

Adult liver cells are accessible and abundant and can be taken from the patient and, after conversion into β-cells, reintroduced into him/her. This would hopefully avoid the graft versus host problem that is encountered when cells or organs from a donor are transplanted. There would still be the need to address the autoimmune response that has caused the disease in the first place. In this respect, numerous worldwide efforts are devoted to re-educate the immune system to not attack β-cells (reference 6), while other research tries to find drugs that dampen the effect of the autoimmune response without causing serious side effects. Then there are studies directed to protect insulin producing cells by encapsulating them into devices equipped with semi-permeable membranes to protect them from the attack of the host immune system when implanted in T1D people. Two biotechnology companies have already started Food and Drug Administration approved clinical trials with pancreatic islets (cells that harbor β cells) (reference 7).  Moreover, pancreatic β-cells’ encapsulation technology and its successful application to T1D animal models has recently been reported (reference 8).

Footnotes
1. A transcription factor is a protein that binds to a specific DNA sequence to control the rate of its transcription into messenger RNA which consequently may be translated into the generation of a protein.
2. Progenitor cells are still immature cells that are committed to become a specific cell; in this context, either liver or pancreas cells
3. Ex vivo means out of the organism’s body. In other words, the experiment is carried out in cells or tissues isolated from the organism; while, experiments carried out in the intact organism are referred as to in vivo.
4. Transduction is the process by which foreign DNA is introduced into a cell by a virus or viral vector.

References
1. Cerda´-Esteban, N. et al. Stepwise reprogramming of liver cells to a pancreas progenitor state by the transcriptional regulator Tgif2. Nat. Commun. 8, 14127 doi: 10.1038/ncomms14127 (2017).

2. For stem cells, part 4 of: http://www.steelimmunity.com/blog/2015/12/28/type-1-diabetes-research-advances-to-develop-a-cure. Dec 29 2015 Type 1 Diabetes: Research Advances to develop a cure

3. For stomach cells: http://www.steelimmunity.com/blog/2016/3/9/vw7azdrf5at25wpv5fqt9opeksl7xc . Mar 9, 2016 Stomach tissues reprogrammed to produce Beta-cells restore normal glucose levels in type 1 diabetic mice.

4. For skin cells: http://www.steelimmunity.com/blog/2016/5/24/2016-another-step-forward-in-the-quest-to-cure-type-1-diabetes-scientists-coax-skin-cells-from-type-1-diabetes-patients-to-become-insulin-producing-cells . May 24, 2016 Another step forward in the quest to cure Type 1 Diabetes: Scientists coax skin cells from Type 1 Diabetes patients to become insulin producing cells

5. For pancreatic α-cells  http://www.steelimmunity.com/blog/2016/12/16/dec-16-towards-new-therapies-for-type-1-diabetes-scientists-found-approved-medical-drugs-able-to-convert-pancreatic-cells-into-like-cells-that-produce-insulin

6. For the immune system re-education, part 7 of: http://www.steelimmunity.com/blog/2015/12/28/type-1-diabetes-research-advances-to-develop-a-cure

7. For islets encapsulation, part 6 of http://www.steelimmunity.com/blog/2015/12/28/type-1-diabetes-research-advances-to-develop-a-cure.

8. For β cells encapsulation: http://www.steelimmunity.com/blog/2016/2/1/progress-in-cells-encapsulation-for-type-1-diabetes-t1d-treatment . Feb 1, 2016 Progress in β cells encapsulation for Type 1 diabetes (T1D) treatment.

 

2017 Fasting Mimicking Diet Restores Insulin Production in Pancreatic Islets from People with T1D and in Mice Models of Type 1 and 2 Diabetes (T1D and T2D)

Dec 16 2016 Towards new therapies for Type 1 Diabetes: Scientists found approved medical drugs able to convert pancreatic α-cells into β-like-cells that produce insulin