I think any game can stand on its own if run correctly and actively. Some people like cross-over a lot, though, and will judge their ability to play with (if not actually play as) a certain sphere, or just other spheres in general.
Some games work better alone. I think Mage and Hunter are two excellent examples of that. Mage's versatility and sheer amount of potential power (which, given how MUs tend to treat XP, can quickly turn into actual power) and Hunter's general theme of being antagonistic to every supernatural splat on the basis of being, well, Hunters, make them both best for one-sphere games. In fact, I think they would be more fun as one-sphere games, where everything is an insane arcane mystery or everything that goes bump in the night is a target.
For the game I'm working on, we have three supernatural spheres (Demon, Vampire, and Werewolf), plus their sub-splats (Stigmatics, Ghouls, and Wolf-Blooded), plus Mortals (which can all have psychic powers if the players want, since we won't be differentiating between those with and those without for the purposes of the "Mortal Sphere". That's a lot of options, even if it doesn't seem like it after playing somewhere like Haunted Memories or The Reach.
Each one of those spheres was picked for a reason. Demon was picked because at least some of us (myself included) just really, really want to play that game, and this is the only way to get to do that (short of starting our own online tabletop, but I've wanted to make a MU since forever, so). Vampire was picked because it has a political element that we enjoy; and it also brings in a large amount of often good players who just really like to play vampires. Werewolf was picked because it's a great counterpart to the other two, especially vampire, with its animalistic, shamanistic savagery and its entirely different way of organizing its society, plus, it's also a super-popular game, like vampire.
So, yes, in part, some of these choices had a bit of "what will attract the most players?" because the only thing worse than "too many people!" is "not enough people".
The deciding factor was that we wanted a game with multiple (but not many!) spheres, and we definitely wanted it to be second edition. At this point, that left us with three options: Demon, which was out; Vampire, which was out; and Werewolf, which purported to be almost out, but OPP are a bunch of mean, jerkfas liars who are late WHERE THE FUCK IS MY WEREWOLF BOOK ahem. Sorry.
Mage is coming out soon, too, supposedly. But like I said above, Mage, IMO, works best on its own. So we're leaving it out.