I think it'd be acceptable to just handle the errors gracefully when we do hit that limit and make sure the user is clear on why it's happening. Ideally we'd also want to give them some advance warning - either when the maildir is initially set up on a filesystem which suffers from likely limits, or when the limit is being approached. But it might be enough of a corner-case that the effort for advance warning isn't justified...

Something I am concerned about is performance - I don't really have any concrete numbers, but there's always talk circulating about certain filesystems getting slow when directories have too many files in them. Would be nice to nail down some real data on this.
I think there's probably scope for implementing a scheme for stashing mail files in subdirectories. I think a "YYYY-MM" directory structure would be usable and very useful, but that's not orthodox maildir, so would likely be a variant or separate mailstore type...