Toward Precision Medicine with Human Pluripotent Stem Cells for Diabetes

Abstract

Although genome profiling provides important genetic and phenotypic details for applying precision medicine to diabetes, it is imperative to integrate in vitro human cell models, accurately recapitulating the genetic alterations associated with diabetes. The absence of the appropriate preclinical human models and the unavailability of genetically relevant cells substantially limit the progress in developing personalized treatment for diabetes. Human pluripotent stem cells (hPSCs) provide a scalable source for generating diabetes-relevant cells carrying the genetic signatures of the patients. Remarkably, allogenic hPSC-derived pancreatic progenitors and β cells are being used in clinical trials with promising preliminary results. Autologous hiPSC therapy options exist for those with monogenic and type 2 diabetes; however, encapsulation or immunosuppression must be accompanied with in the case of type 1 diabetes. Furthermore, genome-wide association studies-identified candidate variants can be introduced in hPSCs for deciphering the associated molecular defects. The hPSC-based disease models serve as excellent resources for drug development facilitating personalized treatment. Indeed, hPSC-based diabetes models have successfully provided valuable knowledge by modeling different types of diabetes, which are discussed in this review. Herein, we also evaluate their strengths and shortcomings in dissecting the underlying pathogenic molecular mechanisms and discuss strategies for improving hPSC-based disease modeling investigations.

Keywords: drug development; hPSCs; insulin-secreting cells; pathogenesis; personalized therapy.

Graphical Abstract

Figure 1.

Using patient-derived hPSCs for β-cell replacement therapy and personalized treatment for patients with diabetes. Induced pluripotent stem cells (iPSCs) can be generated from patients with different forms of diabetes. Induced pluripotent stem cells generated from patients with monogenic diabetes (MD) due to specific mutations can be corrected to generate healthy iPSCs. Corrected MD-iPSCs and those generated from patients with type 2 diabetes (T2D) can be differentiated into pancreatic progenitors and then insulin-secreting β cells. The differentiated cells can be used for autologous cell therapy where the cells are transplanted back into T2D and MD patients without the need for immunosuppression. However, Patients with T1D would still require immunosuppression, or the pancreatic cells can be transplanted in a capsule to avoid using immunosuppressants.

Figure 2.

Using hPSCs for personalized therapy for diabetes. Patients with MD are recruited to perform whole-genome sequencing to identify the disease-causing SNPs and variants. Additionally, genome-wide association studies (GWAS) data on T1D- and T2D-associated risk loci can be analyzed to identify candidate variants. hPSCs can be gene-edited to carry the disease-causing variant and, along with its isogenic controls, be differentiated to the target lineage. Likewise, MD patient-derived iPSCs can be edited to correct the mutation and further differentiated to perform functional studies. The differentiated cells are investigated to dissect underlying mechanisms and identify dysregulated pathways. These defective pathways can be reversed using specific molecules or drug libraries to develop candidate-specific personalized therapy.

Figure 3.

Advances and limitations in generating pancreatic β cells from hPSCs. Multiple modifications in β-cell differentiation protocols are listed, along with limitations in obtaining hPSC-derived β cells representing adult human β cells persist. Use of ROCKII and YAP inhibition, as well as cytoskeletal depolymerizer during endocrine commitment improves proportion and functionality of the generated β cells. Furthermore, physical manipulation such as disassociation and reaggregation of the hPSC-derived endocrine clusters also improves maturity of β cells and eliminates non-β cells, such as α cells, delta cells or non-committed progenitors and polyhormonal cells, that are normally present in differentiated endocrine clusters along with β cells. However, key maturation markers are still absent from the differentiated β cells along with aberrant calcium signaling and dysfunctional mitochondria.