Dynamic reciprocity in the wound microenvironment

Abstract

Here, we define dynamic reciprocity (DR) as an ongoing, bidirectional interaction amongst cells and their surrounding microenvironment. In the review, we posit that DR is especially meaningful during wound healing as the DR-driven biochemical, biophysical and cellular responses to injury play pivotal roles in regulating tissue regenerative responses. Such cell-extracellular matrix interactions not only guide and regulate cellular morphology, but cellular differentiation, migration, proliferation, and survival during tissue development, including e.g. embryogenesis, angiogenesis, as well as during pathologic processes including cancer diabetes, hypertension and chronic wound healing. Herein, we examine DR within the wound microenvironment while considering specific examples across acute and chronic wound healing. This review also considers how a number of hypotheses that attempt to explain chronic wound pathophysiology, which may be understood within the DR framework. The implications of applying the principles of dynamic reciprocity to optimize wound care practice and future development of innovative wound healing therapeutics are also briefly considered.

Integrins in Wound Healing

“…This reduces the binding of different ECM molecules to each other and integrin-mediated epithelial adhesion to ECM, resulting in defective re-epithelialization. 2 Notably, chronic wounds exhibit drastically decreased epithelial expression of a 5 b 1 integrin, which results in reduced integration of fibronectin into the provisional basement membrane, increased fibronectin degradation, and a failure in keratinocyte migration and re-epithelialization. 146 In addition, increased keratinocyte integrin expression may contribute to the formation of chronic wounds.…”

“…The formation and regulation of cell adhesions via integrin receptors play a fundamental role during all phases of wound healing. 1,2 In the present review, our main focus will be on integrin expression and functions during reepithelialization and granulation tissue formation.…”

Wound Healing Angiogenesis: Innovations and Challenges in Acute and Chronic Wound Healing

“…Several approaches including delivery of proangiogenic growth factors 8 have been employed to enhance wound healing; however, current treatments remain technologically or biologically hampered. 9 Thus, the challenge persists to create innovative and effective therapeutics for acute and chronic wound repair.…”

The stereotypical molecular cascade in neovascular age-related macular degeneration: the role of dynamic reciprocity

“…Although originating within the confines of the cell, the process of DyR dictates that it will spill out into the ECM and so a pathological feedback loop between cell and matrix, which could include an immune component, is established (bidirectional cross-talk), giving rise to a pathological molecular cascade ending in GA or NVAMD, or both. [82][83][84]136 The abnormal local response may also compromise the systemic input from the bone marrow or both local and systemic components could be blunted by co-existent disease. 34,71,121,137 In summary, it appears that the process that is DyR generates the stereotypical and even predictable wound response that is seen in AMD.…”

“…In AMD, the neovessels (SRNV) associated with the proliferative phase of repair are not only abnormal with respect to their location but are also characterized by decreased capillary density, altered morphology, and increased permeability, and is such a microangiopathy rather than a normal NV response occurring as part of physiologic wound healing. 136 Moreover, bleeding from these vessels, which is not a feature of normal repair, will compound the dysfunctional reparative response in an increasingly disordered matricellular environment that ultimately leads to aggressive end-stage fibrosis. 75 The injury in NVAMD is therefore a 'two-hit' process.…”