Editors' ChoiceDevelopment

BMPs Rescue Regeneration

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Science Signaling  09 Feb 2010:
Vol. 3, Issue 108, pp. ec48
DOI: 10.1126/scisignal.3108ec48

Regeneration of limbs or digits occurs in three stages: wound closure, generation of a blastema (a mass of undifferentiated or redifferentiated cells at the amputation site), and differentiation or redifferentiation of cells to reform the missing structures. In neonatal and adult mice, regeneration of the digit tip occurs by a mechanism distinct from that by which the digit is generated in the embryo. Digits amputated proximal to the middle of the third phalangeal (P3) element do not regenerate, but digits amputated distal to the middle of P3 regenerate through a process of intramembranous ossification, in which bone is formed without a cartilage intermediate. In contrast, limb and digit formation in the embryo occurs through a process of endochondral ossification, in which bone formation proceeds through a cartilage intermediate. Yu et al. report that treatment with bone morphogenetic protein 2 (BMP2) or BMP7 conferred regenerative capacity to digits amputated proximal to the middle of P3. BMPs were required for normal digit regeneration, because application of the BMP inhibitor Noggin to digits amputated distal to P3 prevented regeneration, and genes encoding BMP2 and BMP7 were up-regulated in the blastemas of amputated digits as compared to unoperated digits and to the portions of operated digits proximal to the amputation site. Application of beads coated with BMP2 or BMP7, but not BMP4, induced regeneration of digits amputated proximal to the middle of P3, and regeneration continued even after removal of the beads. Furthermore, digits amputated proximal to the middle of P3 and treated with BMP7 regenerated by a mechanism fundamentally different from that followed by digits regenerated without treatment after amputation distal to the middle of P3. The skeletal elements of digits amputated distal to P3 and left untreated proceeded through direct membranous ossification, whereas digits amputated proximal to P3 and treated with BMPs proceeded through endochondral ossification, as indicated by the expression of endochondral marker genes. Thus, exogenous application of BMPs can induce redeployment of the embryonic developmental limb program at an amputation site, a process which is distinct from the adult type of regeneration normally observed in untreated amputated digits, indicating that it may be possible to induce regeneration in tissues not normally competent to regenerate.

L. Yu, M. Han, M. Yan, E. C. Lee, J. Lee, K. Muneoka, BMP signaling induces digit regeneration in neonatal mice. Development 137, 551–559 (2010). [Abstract] [Full Text]

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