We've discussed sequels many times in the past, but I can't help throwing my two cents in.
I think that if there ever were to be a sequel, it should have new main characters with possible cameos by older ones. I'd actually like to play as one of Hector's lower henchmen who was in it just for the money, not because he was evil or something. He probably didn't even know what the big bosses were doing, he just did his job. With Hector gone, he would have fallen from grace and would have to struggle to make it in the Land of the Dead until he happens upon something big, like Manny did. I think that kind of story has lots of potential for character growth.
This would also be sensible because then new players could get into the game right away without having played the first.