Analogous cellular contribution and healing mechanisms following digit amputation and phalangeal fracture in mice

Dawson, Lindsay A.; Simkin, Jennifer; Sauque, Michelle; Pela, Maegan; Palkowski, Teresa; Muneoka, Ken

doi:10.1002/reg2.51

Cited by 28 publications

(61 citation statements)

References 51 publications

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“…Because BMP2 and 7‐induced regeneration of nonregenerative proximal P3 amputations occur via endochondral ossification, it is suggestive that the regenerative wound environment is not inhibitory for chondrogenesis . Furthermore, the demonstration that skeletal regeneration can be induced by targeted treatment of nonregenerative digit or limb amputations with BMPs suggest an interface between mechanisms guiding tissue‐specific bone repair and an epimorphic regenerative response that can be exploited to enhance regenerative capabilities in mammals …”

Section: Discussionmentioning

confidence: 99%

Blastema formation and periosteal ossification in the regenerating adult mouse digit

Dawson

Schanes

Kim

et al. 2018

Wound Repair Regeneration

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While mammals cannot regenerate amputated limbs, mice and humans have regenerative ability restricted to amputations transecting the digit tip, including the terminal phalanx (P3). In mice, the regeneration process is epimorphic and mediated by the formation of a blastema comprised of undifferentiated proliferating cells that differentiate to regenerate the amputated structures. Blastema formation distinguishes the regenerative response from a scar-forming healing response. The mouse digit tip serves as a preclinical model to investigate mammalian blastema formation and endogenous regenerative capabilities. We report that P3 blastema formation initiates prior to epidermal closure and concurrent with the bone histolytic response. In this early healing response, proliferation and cells entering the early stages of osteogenesis are localized to the periosteal and endosteal bone compartments. After the completion of stump bone histolysis, epidermal closure is completed and cells associated with the periosteal and endosteal compartments blend to form the blastema proper. Osteogenesis associated with the periosteum occurs as a polarized progressive wave of new bone formation that extends from the amputated stump and restores skeletal length. Bone patterning is restored along the proximal-distal and medial digit axes, but is imperfect in the dorsal-ventral axis with the regeneration of excessive new bone that accounts for the enhanced regenerated bone volume noted in previous studies. Periosteum depletion studies show that this compartment is required for the regeneration of new bone distal to the original amputation plane. These studies provide evidence that blastema formation initiates early in the healing response and that the periosteum is an essential tissue for successful epimorphic regeneration in mammals.

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Section: Discussionmentioning

confidence: 99%

Blastema formation and periosteal ossification in the regenerating adult mouse digit

Dawson

Schanes

Kim

et al. 2018

Wound Repair Regeneration

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“…Re-differentiation of the blastema to 103 regenerate the amputated P3 bone occurs by direct ossification and is dependent on BMP and WNT 104 signaling (Lehoczky and Tabin, 2015;Takeo et al, 2013;Yu et al, 2010). Amputation of digits at more 105 proximal levels fail to regenerate but results in a periosteal response that forms a bone callus similar to 106 a fracture healing response (Dawson et al, 2016). 107…”

mentioning

confidence: 99%

Macrophages are required to coordinate mouse digit tip regeneration

Muneoka

Simkin

Sammarco

et al. 2017

Preprint

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In mammals, macrophages are known to play a major role in tissue regeneration. These cells contribute to inflammation, histolysis, re-epithelialization, re-vascularization and cell proliferation. While macrophages have been shown to be essential for epimorphic regeneration in salamanders and fish, their role has not been elucidated in mammalian epimorphic regeneration. Here, using the mouse digit tip model as a mammalian model of epimorphic regeneration, we demonstrate that macrophages are essential for the regeneration process. Using cell depletion strategies, we show that regeneration is completely inhibited; bone histolysis does not occur, wound re-epithelization is inhibited and the blastema does not form. Rescue of epidermal wound closure, in the absence of macrophages, promotes blastema accumulation but not differentiation indicating that macrophage play a role in re-differentiation. Additionally, inhibition of osteoclasts and the degradation process is not sufficient to inhibit regeneration. These findings show that macrophages play an essential role in coordinating the epimorphic regenerative response in mammals.

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“…Although injury promotes formation of a new bone callus in nonregenerative P2 amputations, and new cartilage nodules in the nonregenerative Mus ear pinna, in both cases these new tissues are usually disorganized and mispatterned . With respect to bone and cartilage, these observations support direct differentiation of periosteal and perichondrial cells into new tissue, but underscores the failure to organize a multicellular response typical of epimorphic regeneration.…”

Section: How Do Mammals Establish a Regenerative Microenvironment?mentioning

confidence: 79%

Concise Review: Translating Regenerative Biology into Clinically Relevant Therapies: Are We on the Right Path?

Simkin

Seifert

2017

Stem Cells Translational Medicine

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Despite approaches in regenerative medicine using stem cells, bio‐engineered scaffolds, and targeted drug delivery to enhance human tissue repair, clinicians remain unable to regenerate large‐scale, multi‐tissue defects in situ. The study of regenerative biology using mammalian models of complex tissue regeneration offers an opportunity to discover key factors that stimulate a regenerative rather than fibrotic response to injury. For example, although primates and rodents can regenerate their distal digit tips, they heal more proximal amputations with scar tissue. Rabbits and African spiny mice re‐grow tissue to fill large musculoskeletal defects through their ear pinna, while other mammals fail to regenerate identical defects and instead heal ear holes through fibrotic repair. This Review explores the utility of these comparative healing models using the spiny mouse ear pinna and the mouse digit tip to consider how mechanistic insight into reparative regeneration might serve to advance regenerative medicine. Specifically, we consider how inflammation and immunity, extracellular matrix composition, and controlled cell proliferation intersect to establish a pro‐regenerative microenvironment in response to injuries. Understanding how some mammals naturally regenerate complex tissue can provide a blueprint for how we might manipulate the injury microenvironment to enhance regenerative abilities in humans. Stem Cells Translational Medicine 2018;7:220–231

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Analogous cellular contribution and healing mechanisms following digit amputation and phalangeal fracture in mice

Cited by 28 publications

References 51 publications

Blastema formation and periosteal ossification in the regenerating adult mouse digit

Blastema formation and periosteal ossification in the regenerating adult mouse digit

Macrophages are required to coordinate mouse digit tip regeneration

Concise Review: Translating Regenerative Biology into Clinically Relevant Therapies: Are We on the Right Path?

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