Common Aspects of Animal Regeneration

Embryogenesis is a complex process in which a single cell, the zygote, initiates a developmental trajectory that will lead to a hatching, multicellular organism. Embryogenesis may lead to a final adult morphology in direct developing species, or to an intermediate, larval form in indirect developing species. Indirect development implies post-embryonic developmental trajectories, like metamorphosis, that transform the larvae into the adult form. Regeneration is another post-embryonic developmental trajectory, but differs from embryogenesis and metamorphosis in that it starts from a highly unpredictable situation, as traumatic injury triggering regeneration can happen in many possible ways, each resulting in a different initial condition. Thus, although converging to the same final morphology as embryogenesis and/or metamorphosis, regeneration’s developmental trajectory requires additional degrees of freedom to adapt to unpredictable initial conditions.

For successful regeneration, an organism needs to sequentially overcome three main challenges: (1) survive the injury and close the wound to avoid uncontrolled flow between the internal and external environments of the body; (2) gather the resources it will need to reconstruct the structures lost to injury; and (3) deploy and convert these resources into structures functionally equivalent to those lost. Since these three challenges are common to all injured organisms, it is not surprising that regeneration studies in very distantly related organisms usually report the same three main phases for this developmental trajectory: (1) wound healing; (2) cellular reorganization from stem cells, dedifferentiated cells or transdifferentiated cells; and (3) cellular differentiation, morphogenesis, growth, and rescaling.

Wound Healing

Organisms keep a strict separation between their internal and external environments. Separation is usually achieved by a layer of epithelial tissue that controls passage between these domains. The integrity of this epithelial barrier is fundamental to keep the proper balance of substances between the inside and the outside, and to prevent infection by pathogens or entry of toxic molecules. Traumatic injury compromises the barrier by generating an opening, the wound. Most if not all organisms deploy some form of wound healing after enduring (and surviving) a wound-opening injury.

The most urgent aim of wound healing is generating a quick response to stop direct contact between the internal and external environment. This can be achieved through different strategies, including covering of the wound by mucus secretions or protein coagulates, blockading the wound by agglomeration of cells into a w'ound plug, and/or closing of the wound by contraction of nearby muscle fibers. In many cases, wounding also activates a response from the immune system, usually involving the migration of several cell types to the injured area to fight potential infection.

The initial quick w'ound response is followed by growth and/or expansion of the epithelial layers adjacent to the w'ound, followed by fusion, until the opening is closed. During or after this second step, wound cleanup takes place to remove internal leftover structures like wound plugs, broken cells, and other debris. Immune cells, especially phagocytes, will often take part in this effort. At the end of this step, tissues adjacent to the wound site, often collectively referred to as the stump, no longer suffer uncontrolled exchange with the external environment. In many cases, an epidermal layer known as the wound epithelium forms over the wound that is histologically and transcriptionally different from the original epidermis. The w'ound epithelium has been shown to play critical roles in the earlier phases of regenerative responses (Carlson 2007; Campbell and Crews 2008; Eming, Martin, and Tomic- Canic 2014).

Wound healing is a critical phase for all regenerative processes. Improper wound healing can delay or stall further regeneration. This might be due to several reasons: on the one hand, the w'ound-healing process generates a cleaner starting point for the next phase of regeneration; on the other, tissues involved in wound healing are often responsible for releasing molecular signals that trigger regeneration (Brockes and Kumar 2008). Wound-healing strategies might also interfere with regenerative potential: in mammals, for example, poor regeneration is thought to be at least partially caused by the inflammatory nature of the immune response and the formation of a non-cellular scab of clotted proteins (Goss 1987; Harty et al. 2003). Faulty signaling during and after wound healing can be a cause for a loss of regenerative ability, as the amputated organism fails to transition from this initial phase to the next, cell reorganization, and blastema formation.

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