Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Dec 23;9(1):366.
doi: 10.1038/s41392-024-02090-x.

Advancing type 1 diabetes therapy: autologous islet transplant breakthrough

Ram Abou Zaki  1   2 , Assam El-Osta  3   4   5   6
Affiliations

Advancing type 1 diabetes therapy: autologous islet transplant breakthrough

Ram Abou Zaki et al. Signal Transduct Target Ther. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Adipose-derived mesenchymal stromal cells were isolated from a 25-year-old T1D patient and reprogrammed into chemically induced pluripotent stem cells (CiPSC’s) over a 59-day period employing a complex differentiation strategy of pharmacological stimulation designed in four discrete stages. Modulators influencing major signalling pathways were employed to manufacture patient-derived CiSPC-islets. The first category was the disruption of the signal transduction pathways of protein kinases by several modes of inhibition. CHIR99021, ABT869, Y27632, Ruxolitinib, JNKIN8, PD0325901, and SB590885 are signalling pathway inhibitors targeting key molecular pathways (Wnt/β-catenin, angiogenesis, ROCK, JAK-STAT, MAPK). Impressive advances were also made against core pathways involved in epigenetic regulation. EPZ5676 (Pinometostat) and EPZ004777 inhibit protein methyltransferase DOT1L, DZNep targets the inhibition of the EZH2 histone methyltransferase, UNC0224 inhibits histone methyltransferase G9a, 5-azacytidine promotes DNA hypomethylation by inhibiting DNA methyltransferase, and valproic acid (VPA) acts as a histone deacetylase inhibitor, promoting histone acetylation and indirectly influencing DNA demethylation. Pathways involved in growth factor signalling were also targeted using SAG (Smoothened Agonist), Bone Morphogenetic Protein 4 (BMP4) and Activin A which are part of the TGF-β superfamily and is involved in stem cell function. In the second phase, Activin A, KGF, retinoic acid, EGF, T3, and nicotinamide were added to regulate growth factor signalling and cell fate. The protein kinase inhibitors PI103, SB431542 and LDN193189 targeted key signalling pathways that influence stem cell differentiation. EPZ004777 inhibits protein methyltransferase DOT1L. Antioxidants were added and include Vitamin C, N-acetylcysteine (NAC), Heparin, and Zinc Sulfate protected cells from oxidative stress and promoted survival during differentiation. The small molecule TPB was used to modulate cellular behaviour. The islets comprised approxiamately of 60% β-cells, 10% α-cells and 10% δ-cells and were injected underneath the abdominal anterior rectus sheath of the patient who remained diabetes free at 1-year follow-up
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Wang, S. et al. Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. Cell187, 6152–6164.e18 (2024). - PubMed
    1. Wang, D. et al. Long-Term Expansion of Pancreatic Islet Organoids from Resident Procr(+) Progenitors. Cell180, 1198–1211.e1119 (2020). - PubMed
    1. Wu, J. et al. Treating a type 2 diabetic patient with impaired pancreatic islet function by personalized endoderm stem cell-derived islet tissue. Cell Discov.10, 45 (2024). - PMC - PubMed
    1. Guan, J. et al. Chemical reprogramming of human somatic cells to pluripotent stem cells. Nature605, 325–331 (2022). - PubMed
    1. Al-Hasani, K. et al. EZH2 inhibitors promote β-like cell regeneration in young and adult type 1 diabetes donors. Sig. Transduct. Target Ther.9, 2 (2024). - PMC - PubMed

LinkOut - more resources