It is, pretty obviously, about the college experience of the two main characters of Monsters, Inc.: Mike Wazowski, a short green ball with one big eye and spindly limbs, and Sulley, a giant blue-with-purple-spots furry ogre of some sort. Both movies' themes highlight the importance of a diversity of talent, and the value of every individual.
This post from here on contains spoilers for both this movie and Monsters, Inc., so I'm putting it behind a Read More line.
This movie should, in theory, suffer from the problems of being a prequel: the characters are limited to only experiencing enough growth to get them where they are at the start of the original movie; the audience has grown with a particular set of characters' experiences, which necessarily need to be ignored during the prequel, and everybody knows, if not how the story is going to end, at least how a lot of the threads are destined to work out.
On the other hand, this movie couldn't possibly have been a sequel: after Monsters, Inc. everything changes -- the world that the movies are built on is no more. There's nowhere to go but backwards.
I think Pixar did a pretty good job of skirting around some of these, and other than that pretty much wholly embraced them. The fact that the ending is a known value may not even be a problem -- studies have shown that people reading stories that have been spoiled enjoy them more than if they don't know how it's going to end, so prequels may be improved by the fact that we know, at least, that our main character will probably be okay.
Plus, the world of Monsters, Inc. is pretty ethically troubling. But it's reassuring to know that we're watching the story of the people who will one day come to end the paradigm of terrifying little children to feed an industrial economy. (I'm not sure if that's supposed to be the big metaphor or anything, but it is literally what happens in the movie.)
Whether Pixar thought ahead or just chose a prequel candidate well, Mike and Sulley are in an emotional and psychological place that can be built up to at the start of Monsters, Inc. They're good, likeable characters who go through a worldview-shaking experience.
So, all Monsters University had to do was give them to us as annoying teenagers. Sure, they're horrible, selfish dicks, but they're kids. They might grow out of it -- and we know that they will.
This movie reminded me several times of something John Green says a lot (though I can't begin to remember where, so I can't link a quote): The hero's journey is not from weakness to strength, but from strength to weakness.
Mike is a dedicated bookworm and Sulley is a natural scarer with a legacy family, and coming into school both of them are entirely confident in their ability to be the best in their class. Through the course of the plot, they lose confidence in their inevitable success, then lose confidence in their ability to brute-force their way to success, then, ultimately, shed the belief that they are innately better than the people around them.
By the end, they embrace their weaknesses and stop getting in each other's, and their teammates', way, and achieve things together that not even a well-adjusted individual could manage alone.