Evaluating alternative stem cell hypotheses for adult corneal epithelial maintenance

Table 1 Evidence discriminating between alternative hypotheses

Observations	Species	Ref.	Consistent with hypothesis?
			LESC	CESC	GBL
Holoclone-producing cells are present in limbus but not cornea	Human	[25]	++	±	±
Holoclone-producing cells are present in limbus and cornea	Pig	[1]	±	++	±
Production of clonogenic spheres from limbus and central cornea	Human	[29]	±	++	±
Limbal epithelial cells are superior to corneal epithelial cells for corneal repair	Human	[32,33]	++	+	±
The central corneal epithelium can maintain itself when isolated from the limbus Label-retaining cells are present in the limbus but not the corneal epithelium during normal homeostasis	Rabbit, mouse, human Mouse, rabbit	[1,39-42] [13,52-54,57]	+a ++	++ +	++ 0
After a 40-d chase 3H-TdR-labelled cells are present in both the limbus and the corneal epithelium during normal homeostasis	Rabbit	[2]	+b	+b	+b
Cells move centripetally from the periphery of the corneal epithelium during normal homeostasis	Human, mouse	[58,61-63]	++	±c	±c
Mosaic patterns change after birth and clones of labelled cells emerge from the limbus as radial stripes	Mouse	[27,72,77-79]	++	0	0
Distribution of rare stripes in corneas of KRT5-LacZ+/- transgenic mice	Mouse	[17]	++	±	±
Transplanted limbal tissue contributes to replacing experimentally debrided corneal epithelium	Rabbit, mouse	[1,76]	++	++	+
Transplanted limbal tissue does not contribute to the unwounded corneal epithelium	Mouse	[1]	0	++	++
More tumours arise from the limbal epithelium than corneal epithelium	Human	[80]	++d	+	+
Diverse cell types and blood supply makes limbus a likely stem cell niche	All species	[6]	++d	+	+
Distribution of markers associated with undifferentiated or stem cell phenotype	Human, mouse, rabbit	See Table 2	++	±	±
Lineage tracing studies show that limbal cells contribute to the unwounded corneal epithelium during normal homeostasis	Mouse	[64]	++	0	0

++: Expected for hypothesis; +: Consistent with hypothesis; ±: Not consistent with hypothesis unless specific assumptions are made or technical issues compromise the interpretation of the experiment; 0: Not consistent with hypothesis.

^aThis is compatible with the LESC hypothesis if self-maintenance of the central corneal epithelium is a back-up mechanism that is used when homeostasis is compromised and LESCs are unable to maintain the corneal epithelium.

^bThe chase period may not have been sufficient to identify label-retaining cells (see text).

^cThe CESC hypothesis, as originally stated[1], proposed that corneal epithelial cell movement was centrifugal but this assumption is not necessary. However, it requires ad hoc assumptions to account for centripetal movement across the full radius.

^dEvidence is circumstantial. LESC: Limbal epithelial stem cell.