Identifying the stem cell of the intestinal crypt: Strategies and pitfalls

Decades ago, two nonoverlapping crypt stem cell populations were proposed: Leblond's Crypt Base Columnar (CBC) cell and Potten's +4 cell. The identification of CBC markers including Lgr5 has confirmed Leblond's predictions that CBC cells are anatomically distinct, long-lived stem cells that permanently cycle. While Potten originally described +4 cells as proliferative and unusually radiation-sensitive, recent efforts to identify +4 stem cells have focused on the identification of cells that are quiescent and radiation-resistant. Here, we describe commonalities and discrepancies between the individual studies and discuss challenges of marker-based lineage tracing.