If you mean "you have a single city in a region and play by yourself", I'd say yes, but it's a bit more difficult. You cannot specialize as easily, and you're on your own to build everything (ie, some upgrades give region-wide unlocks). Lack of trade/commuting to other towns also kinda screws you. I guess you could build all the cities in a region, but IMHO, my brain would explode trying to do that.
It's pretty clear the game is designed for co-op. There's nothing wrong with learning the ropes by doing your own private region city at first, but I think the long-term appeal is going to be working in a team in a big region.
Having just started my second city I see no problem, as long as you are willing to play multiple neighbour cities together. You simply canīt fit everything you need in one singe plot. Switching between cities seems fine, if it werent for the fact that changing plots right now is like asking for the game to break. It took me 1 hour of repeated attempts to switch from my main city to another --- http://totalrevue.com/