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Skin Shedding and Tissue Regeneration in African Spiny Mice (Acomys)


Skin Shedding and Tissue Regeneration in African Spiny Mice (Acomys)

Ashley W Seifert et al. Nature.


Evolutionary modification has produced a spectrum of animal defence traits to escape predation, including the ability to autotomize body parts to elude capture. After autotomy, the missing part is either replaced through regeneration (for example, in urodeles, lizards, arthropods and crustaceans) or permanently lost (such as in mammals). Although most autotomy involves the loss of appendages (legs, chelipeds, antennae or tails, for example), skin autotomy can occur in certain taxa of scincid and gekkonid lizards. Here we report the first demonstration of skin autotomy in Mammalia (African spiny mice, Acomys). Mechanical testing showed a propensity for skin to tear under very low tension and the absence of a fracture plane. After skin loss, rapid wound contraction was followed by hair follicle regeneration in dorsal skin wounds. Notably, we found that regenerative capacity in Acomys was extended to ear holes, where the mice exhibited complete regeneration of hair follicles, sebaceous glands, dermis and cartilage. Salamanders capable of limb regeneration form a blastema (a mass of lineage-restricted progenitor cells) after limb loss, and our findings suggest that ear tissue regeneration in Acomys may proceed through the assembly of a similar structure. This study underscores the importance of investigating regenerative phenomena outside of conventional model organisms, and suggests that mammals may retain a higher capacity for regeneration than was previously believed. As re-emergent interest in regenerative medicine seeks to isolate molecular pathways controlling tissue regeneration in mammals, Acomys may prove useful in identifying mechanisms to promote regeneration in lieu of fibrosis and scarring.


Figure 1
Figure 1. A. kempi and A. percivali exhibit skin autotomy and subsequent rapid healing
(a–b) A. kempi (a) and A. percivali (b) possess stiff, spine-like hairs on the dorsum. (c) A. kempi following loss of dorsal skin. (d–e) Scab formation following full thickness skin injury visible at D3 (d). The same wounds in (d) are no longer visible at D30 and new spiny hairs cover the damaged area (e). (f) Healing wound in field-caught specimen showing new hair follicles within the wound bed. Scale bars = 1 cm.
Figure 2
Figure 2. Acomys skin is weak, tears easily, and during repair develops a porous extracellular matrix rich in collagen type III
(a–b) Stress-strain curves for Mus n=6, A. kempi n=5, A. percivali n=5, depicted up to the failure strain (a) and for one individual (b) approximating the real mean tensile strength (σm) and mean toughness (W) (represented as shaded areas). (c–d) Masson’s Trichrome staining of unwounded back skin from M. musculus (c) and A. percivali (d). (e–f) Percent adnexa (e.g. hair follicles and associated glands) in the dermis (yellow shading) of Mus (e) and A. percivali (f). (g) Cytokeratin stained keratinocytes (yellow arrow) just beginning to migrate in small wounds at D3 in Mus. (h) Completely re-epithelialized wounds in Acomys at D3. Time after injury in days. WM = wound margin. Insets show relative wound position of the pictured tissue. (i–l) Picrosirius red staining of small wounds in Mus (i, k) and A. percivali (j, l). Bifringence of picrosirius stain (k, l) differentiates thick collagen type I fibers (red/orange) from thin collagen type III fibers (green). Collagen fibers in Mus are predominantly type I, densely packed and run parallel to the epidermis (k). Collagen fibers in A. percivali are more porous with a greater proportion of collagen type III (l). Scale bars = 100µm.
Figure 3
Figure 3. Acomys exhibit de novo hair follicle regeneration in wounded skin
(a–d) Hair follicles regenerating in A. percivali (yellow arrows) between D21 and D28 in large skin wounds. Days are post injury. New hair follicles (yellow arrows) are present throughout the wound bed (red dotted area) at D28 (c–d). Green arrows indicate old follicles. WM = wound margin. (e–k) Regenerating hair follicles express proteins associated with development and differentiation; Ki67 labels proliferating hair germ (e), Keratin-17 (yellow arrows) in Acomys, but is absent in Mus at D26 (f), nuclear localized LEF1 in follicle placodes (g) and later in dermal papilla cells (dp) and surrounding matrix cells (mx) (h), phosphorylated SMAD 1/5/8 (as a readout of Bmp-signaling) in epidermal hair germ cells (i) and later in dermal papilla cells (dp) and matrix cells (mx) of regenerating follicles (j), and Sox2 in dermal papilla cells (k). Scale bars = 100 µm, except (e) = 50 µm.
Figure 4
Figure 4. Acomys regenerate hair follicles, sebaceous glands, dermis, adipose tissue and cartilage in 4mm ear punches
(a) Regenerated 4mm ear punch in A. percivali. (b) Unwounded tissue in Acomys ear pinna. (c) Regenerated dermis, hair follicles, cartilage and adipose tissue within biopsy punched area. Days are post injury. White circle = original punch area. (d) Regenerating hair follicles (yellow arrows) and cartilage (green arrows) differentiate proximal to distal. (e) Safranin-O/Fast Green indicates chondrogenesis (green arrows). (f–i) Proliferating cells (Ki67+) in early (f–g) and late (h–i) Acomys and Mus ears. Proliferation is restricted proximal to the wound epidermis (WE) (red arrows) in Acomys (f) and is continuous in basal keratinocytes of Mus (g). Proliferation is maintained in Acomys at D32 (h) with very few proliferating cells persisting in Mus (i) (red arrows). (j–l) Collagen IV stained mature basement membrane is absent beneath the wound epidermis in Acomys (j), but is present near the amputation (k) and distally in Mus (l). Yellow arrows indicate basement membrane; e=epidermis, and white brackets indicate epidermal thickness. (m–n) Almost no αSMA positive fibroblasts are present in Acomys (m) whereas αSMA positive myofibroblasts are present in healing Mus ear (n). Inset shows stress fibers in individual myofibroblasts. (o) TN-C disappears where new cartilage differentiates (white arrows) in Acomys. Yellow/green cells (j–o) are autofluorescing blood cells in GFP channel. Scale bars = 100 µm.

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