The Nexus of Stem Cell-Derived Beta-Cells and Genome Engineering

Abstract

Diabetes, type 1 and type 2 (T1D and T2D), are diseases of epidemic proportions, which are complicated and defined by genetics, epigenetics, environment, and lifestyle choices. Current therapies consist of whole pancreas or islet transplantation. However, these approaches require life-time immunosuppression, and are compounded by the paucity of available donors. Pluripotent stem cells have advanced research in the fields of stem cell biology, drug development, disease modeling, and regenerative medicine, and importantly allows for the interrogation of therapeutic interventions. Recent developments in beta-cell differentiation and genomic modifications are now propelling investigations into the mechanisms behind beta-cell failure and autoimmunity, and offer new strategies for reducing the propensity for immunogenicity. This review discusses the derivation of endocrine lineage cells from human pluripotent stem cells for the treatment of diabetes, and how the editing or manipulation of their genomes can transcend many of the remaining challenges of stem cell technologies, leading to superior transplantation and diabetes drug discovery platforms.

Applications of iPSC-derived beta cells from patients with diabetes

“… 70 For SC-β cell therapy, key targets for the genome engineering of diabetes cell therapy included human leukocyte antigen (HLA) modification to expand SC-islet utility and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1/programmed death ligand-1 (PD-1/PD-L1) adjustment to target T cell immune rejection upon transplantation. 71 , 72 Alternate iPSC-derived engineered cell types (endothelial, smooth muscle, cardiomyocytes) described by Deuse et al. 73 used major histocompatibility complex (MHC)-mismatched allogeneic sources to inactivate the MHC class I and II genes and overexpress CD47 with CRISPR/Cas9 to successfully evade immunosuppression in recipients.…”

Mesenchymal Stem Cells: A Trump Card for the Treatment of Diabetes?

“…In particular, recent progresses have been made by using human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hi-PSCs) [9]. Many authors have tried to force these cells to undergo a specific differentiation by using cocktails of growth factors or drugs to inhibit or to activate precise signaling pathways, such as TGF-β signaling pathway [10,11], or by driving the expression of genes peculiar for beta cells though genetic manipulations [12]. The greater part of these studies was able to obtain a limited amount of cells which expressed beta cell markers and responded to glucose stimulation.…”

“…The latter problem could be bypassed by using hi-PSCs, which could be derived directly from the patient who will receive them after in vitro manipulation. Moreover, the new gene editing techniques, such as CRISPR/Cas9, make it possible to correct the genetic defects responsible for diabetes, as well as to introduce pro-differentiative genes [12]. Therefore, hi-PSCs seem to be more promising as a therapeutic option and more complex and effective protocols have been recently proposed focused on these cells, such as the multi-steps protocol by Velazco-Cruz (2019), which was able to obtain an almost pure and functional population of beta-like cells though the time-dependent modulation of TGF-β signaling pathway [15].…”

Nanotechnology in cell replacement therapies for type 1 diabetes

“…Cellular engineering strategies have been developed to reduce the immunogenicity of the transplanted tissue. Genome editing to match (donor to recipient) or eliminate human leukocyte antigen (HLA) genes has been suggested as a promising approach to improve the immune compatibility of stem cell-derived β-cells [45]. The safety of xenogeneic tissue has been improved by gene editing strategies as well [46,47].…”