Table 1.

Methods to generate beta cells from various cell sources. Direct differentiation protocols.

Method to Generate Beta-Cells	Advantages	Disadvantages	References
Progenitor cells	Pancreatic stem-cell population, self-regeneration of pancreatic islets	No direct evidence of presence in humans	[37,38,39]
Transdifferentiation	Cell availability, possibility for personalized cell therapy	Low differentiation efficiency, high cell heterogeneity, functional immaturity, low GSIS, absence of key beta cell markers	[17,18,19,20,21,22,23,24,25,26]
Direct differentiation (ESCs, PSCs)	Usage of undifferentiated cells, mimicking embryological development, relatively robust GSIS, low heterogeneity, possibility for personalized cell therapy	Signs of functional immaturity, differences in metabolic pathways	[32,33,34,35,36]
Direct differentiation protocol	Advancement
D’Amour et al., 2005 [16]	Efficient differentiation of hESCs to definitive endoderm
Chen et al., 2009 [29]	Generation of pancreatic PDX1+-progenitors from hESCs
Nostro et al., 2011 [30]	Roles of TGF-b, WNT, nodal/activin A, and BMP (bone morphogenetic protein) signaling in the pancreatic lineage cell specification
Rezania et al., 2014 [32]; Pagliuca et al., 2014 [33]	Generation of stem cell-derived beta cells closely resembling native beta cells
Russ et al., 2015 [34]	Omission of BMP inhibitors during pancreatic specification results in higher yield of PDX1+/NKX6.1+-cells
Nair et al., 2019 [35]	Endocrine cell clustering mimics pancreatic organogenesis and promotes beta cell differentiation
Liu et al., 2021 [36]	New combination of chemicals and 3D pancreatic progenitor clusters promote beta cell functions