I had an epiphany this morning about this stuff. Regions and individual city space: Cities in the region should compete for land. Fledgling cities must annex land for them to build upon. Neighboring cities could share maps, either totally or partially. That way, a town hell bent on being huge could run into a town hell bent on being small. Or towns could vie for natural resources or formations. This would allow for a city to be affected by it's neighbor's pollution, crime, traffic, etc. as well as being able to reap the benefits of it's neighbor's or neighbors' ports or high value areas. This could be especially challenging when set up with internet play. Additionally, you could set up a transportation network a little easier when you can see the other cities' highway/road/rail terminus points (a regional grid system).
Also, a single city could expand this way into it's neighbor's maps. You could switch maps, yet still retain the primary city's funds and needs to have a geographically enormous megapolis, without the need for the massive computer power required for such a task.
It would also be challenging to have the region already populated to a tiny extent. Most cities start out in the middle of farms. They could already have a minor amount of infrastructure, like roads. Or perhaps a military base or large remote factory that could provide jobs and income, only to be closed or expanded later on. A closed military base could be a fun challenge to reuse: demolition, zoning, cleanup, and the competition from additional cities to acquire such a facility.
Just sharing the idea. I hope I spelled everything right.