The role of stem cells in limb regeneration

Figures & data

TABLE 1. Regenerative properties across vertebrate models of whole limb and digit tip regeneration after amputation.

	Axolotl	Newt	Mouse	Human
Limb regeneration capacity	Complete	Complete	Partial (digit tip)	Partial
Limb amputation response	Epimorphic regeneration	Epimorphic regeneration	Scar formation	Scar formation
Critical amputation site	Proximal limb	Proximal limb	Distal phalanx (proximal nail)	Distal phalanx (proximal nail)
Blastema formation	Complete	Complete	Blastema-like structure	Unknown
Cellular source of regeneration	Tissue-specific stem/progenitors	Tissue-specific stem/progenitors	Tissue-specific stem/progenitors	Unknown
Developmental restriction	Germ layer-restricted	Germ layer-restricted	Germ layer-restricted	Unknown
Primary cellular mechanism	Lineage-restricted	Lineage-restricted	Lineage-restricted	Unknown
Primary mode of regeneration	Lineage-restricted differentiation	Lineage-restricted differentiation	Lineage-restricted differentiation	Unknown
Auxiliary modes of regeneration	None	Dedifferentiation and redifferentiation	None	Unknown

^a Multiple case reports of partial restoration of distal phalanges similar to the mouse digit tip

^b Amputation site beyond which scar formation results

^c After non-critical limb amputation (i.e. proximal limb in urodeles and digit tip in mammals)

^d Thought to follow a similar cellular paradigm to that of mice

^e Skeletal muscle regenerates via dedifferentiaton and redifferentiation of mature myocytes

^f Exhibit cellular lineage conversion of dermis to cartilage and bone

FIGURE 1. Limb regeneration in axolotls. The axolotl follows a cellular mechanism of dedifferentiation and tissue-resident stem/progenitor cell activation for blastema formation (A) and subsequent differentiation to regenerate amputated limb (B).

FIGURE 2. Limb regeneration in newts. Newt amphibians utilize a diverse array of cellular mechanisms for blastema formation (A), demonstrating both dedifferentiation and activation of both tissue-resident stem/progenitor cells and mature myocytes (muscle regeneration only). (While dedifferentiated dermal fibroblasts likely contribute to both dermal and skeletal regeneration, this has not been specifically shown in a newt model.) The cells forming the blastema then differentiate or re-differentiate to reconstitute the missing tissues of the amputated limb (B).

FIGURE 3. Digit tip regeneration in mammals. Mice employ cellular mechanisms that activate tissue-specific stem/progenitor cells for the formation of a blastema-like structure (A) which undergo germ-layer and lineage-restricted differentiation to reconstitute the distal digit tip (B).