Pathological axes of wound repair: gastrulation revisited

Abstract

Post-traumatic inflammation is formed by molecular and cellular complex mechanisms whose final goal seems to be injured tissue regeneration.In the skin -an exterior organ of the body- mechanical or thermal injury induces the expression of different inflammatory phenotypes that resemble similar phenotypes expressed during embryo development. Particularly, molecular and cellular mechanisms involved in gastrulation return. This is a developmental phase that delineates the three embryonic germ layers: ectoderm, endoderm and mesoderm. Consequently, in the post-natal wounded skin, primitive functions related with the embryonic mesoderm, i.e. amniotic and yolk sac-derived, are expressed. Neurogenesis and hematogenesis stand out among the primitive function mechanisms involved.Interestingly, in these phases of the inflammatory response, whose molecular and cellular mechanisms are considered as traces of the early phases of the embryonic development, the mast cell, a cell that is supposedly inflammatory, plays a key role.The correlation that can be established between the embryonic and the inflammatory events suggests that the results obtained from the research regarding both great fields of knowledge must be interchangeable to obtain the maximum advantage.

Figure 1

Consequences of noxious -mechanical and thermal energy- over the skin organ, that is formed by epidermis (parenchyma), and dermis and hypodermis (stroma). A: Adipocyte; F: Fibroblast; K: Keratinocyte; L: Lymphatic capillary; M: Macrophage; MC: Mast cell; N: Neuron; V: Post-capillary venule;

Figure 2

The inflammatory response which is developed after skin injury is divided into evolutive vascular phenotypes and phases. Ischemia-reperfusion (I/R), leukocytic (L) and angiogenic (A) phenotypes are successively expressed during the vascular inflammation. The injured tissue losses its normal structure and acquires functional autonomy during ischemia-reperfusion and leukocytic phenotype expression. Then, when the angiogenic phenotype is progressively expressed, the tissue is re-structured and specialized. In the immediate nervous phase, depolarization and repolarization of cell membranes would be the key pathophysiological mechanism. During the immune phase, the transient synthesis of adhesion molecules favors cellular and bacterial translocation. Lastly, in the endocrine phase the skin tries to recover its parenchymatous structure, or epithelium (regeneration), as well as its stroma or connective tissue (scarring).

Figure 3

Schematic representation of the early mammalian embryo during gastrulation. The extraembryonic mesoderm (EM) is represented surrounding the amniotic cavity (A) and the yolk sac cavity (Y). Between the epiblast (E) and the hypoblast (H) the mesoderm internalizes (IM) by epithelial-mesenchymal transition. On top of the figure, some of the characteristics of the amniotic axis are summarized. On the other hand, on the bottom, some of the characteristics of the yolk sac axis are exposed.

Figure 4

Schematic representation of the gastrulating embryo under the hypothetical influence of an amniotic-interstitial fluid-neurogenic axis (A) and yolk sac-hematopoietic-angiogenic axis (Y). EM. Extraembryonic mesoderm. IM: intra-embryonic mesoderm.

Figure 5

Hypothetical embryonary interstitial confluence of amniotic and yolk sac trophic axis to induce gastrulation.

Figure 6

Schematic representation of the pathological axes expression during vascular inflammation, which is developed in the interstitial space of the injured tissue. c: capillary; ec: epithelial cell; eo: eosinophils; f: fibroblast; l: lymphatic vessel; leu: leucocytes; lym:lymphocyte; mc: mast cell; mØ: macrophage; p: platelets and fibrin; pe: pericyte; sc: stem cell; v: post-capillary venule.

Figure 7

Influence of the pathological axis of neuronal and vascular inflammation in the skin parenchyma (keratinocytes) and stroma (fibroblast). C: Arterial capillary; ECM: Extracellular matrix; F: Fibroblast; K: Keratinocyte; MC: Mast cell; MØ: Macrophage; N: Neuron; V: Vein;

Figure 8

Main role of the mesenchymal cells in the inflammatory interstitium.

Figure 9

The amniotic embryo. The extraembryonic mesenchyma constitutes the walls of the amnion (A) and the yolk sac (Y). During gastrulation it could be considered that the extraembryonic mesenchyma internalizes with its functions: hydroelectrolitic control and neurogenesis in the amniotic side and angiogenesis and hematopoiesis in the yolk sac side. The internalization of the extraembryonic mesenchymal functions could integrate the amnion and the yolk sac original functions into the intraembryonic mesenchyma. Nonetheless, during the inflammatory response, the dedifferentiation process suffered by the tissues could re-express with clarity the primitive axes of the amnion and yolk sac.

Figure 10

Schematic representation of the gastrulation process (top) and of a skin wound (bottom). The hypothetical functional reactivation of embryonic development axes after a tissue injury would reproduce the embryonic biochemical pathways in the mature organism. e: epiblast; eh: endothelial-hematopoietic cell lineages; ep: epithelium; EMT/MET: epithelial mesenchymal transition/mesenchymal epithelial transition; f: fibroblast; HP: hyperpigmentation; m: melanocyte; my: myofibroblast; n:neuron; nc: neural crest cell; NI:neuronal inflammation; nt: neural tube; not: notochord; p: pericyte; skm: skeletal muscle; v:blood vessels; VI: vascular inflammation;

Figure 11

Mast cell key role in orchestrating the inflammatory axis. Upon activation, mast cells could induce the expression of both inflammatory axes, the neurovascular axis and the mesenchymal axis.