Table 2. The limitations of approaches for the generation of beta-cells.

	Ex-vivo generation of beta-cells	ESCs differentiation in vitro	iPSCs differentiation in vitro	Non-beta pancreatic cells transdifferentiation in vivo	Non-beta pancreatic cells transdifferentiation in vitro	Fibroblasts transdifferentiation in vitro	References
Limited sources	Yes	Yes	No	Yes	Yes	No	Huang & Chang (2014)
Risk of teratoma development	No	Yes	Yes	No	No	No	Hentze et al. (2009)
Allograft rejection	No	Yes	No	No	No	No	Hentze et al. (2009)
Lack of organization into islets	No	Yes	Yes	Yes	Yes	Yes	Zhou et al. (2008)
Lack of reproducibility of the protocols	No	No	No	Yes	Yes	Yes	Kim, Jeong & Choi (2020)
Off-target effects after manipulation with genome	No	No	Yes/Noa	Yes	Yes/Noa	Yes/Noa	Clayton et al. (2016)
The necessity of deep invasion for cell product preparation	Yes	No	No	No	Yes	No	Trivedi et al. (2008) and Matsumoto & Shimoda (2020)
The necessity of deep invasion for transplantation of final cell product	Yes	Yes	Yes	No	Yes	Yes	Shapiro, Pokrywczynska & Ricordi (2017) and Matsumoto & Shimoda (2020)

Notes.

^aThe presence of off-target effects will depend on the reprogramming methods (integrating or non-integrating).