Unlike less-developed species such as the axolotl and zebra fish, the adult human has limited ability to regenerate tissue following injury.1, 2<\/sup> Select tissues such as the liver, bone marrow, and the inner lining of the intestinal tract retain regenerative potential in humans, but most other tissues respond to injury (heal) via well the understood processes of hemostasis, inflammation, and deposition of scar tissue. Of note, the developing human foetus and neonate have a more robust ability to regenerate tissue\/organs<\/a> than adults; a healing characteristic rapidly lost following birth. This fact is evidence for the genetically endowed potential for regeneration, but the signals required to activate and realise this potential in adults are unknown.<\/p>\n The most common answer to this question is that there was an evolutionary survival advantage for this trade off. Risk of exsanguination and infection following traumatic injury drove the selection of a swift, albeit imperfect healing process (i.e. haemostasis and scarring) over regeneration. This exchange for survival comes with the cost of increased morbidity and decreased tissue functionality, both of which are dependent upon the location and extent of injury. A clinical example of the pros and cons of this evolutionary selection can be found in patients with traumatic injury in which massive amounts of extremity muscle tissue are destroyed or lost (i.e., volumetric muscle loss). The ability to halt the haemorrhage by blood clot formation and overcome associated wound infection avoids loss of life, but the resulting replacement of skeletal muscle by scar tissue markedly compromises subsequent limb function.<\/p>\n Many strategies for functional tissue replacement exist including cell-based therapies, 3D printing, and tissue\/organ culture<\/a>, however successful clinical translation of these approaches has been very limited. An alternative strategy involves the resurrection or reactivation of at least some of the inherent regenerative capacity that exists in the human genome. Can therapeutic approaches be developed that both retain immediate life-preserving processes and simultaneously activate the molecular signals required to promote and facilitate the otherwise silent genetically-driven pathways of tissue regeneration<\/a>?<\/p>\n To answer these questions, we turn to the immune system. Once thought to have the singular function of protection against pathogens and tissue injury, studies within the past two decades have identified the critical role the immune system plays in normal tissue development and tissue regeneration. Immune system function in higher mammals, including both the innate and adaptive arms, is tightly linked to wound healing and inherent regenerative potential and must be spatially and temporally regulated for any true regeneration to occur. Without such regulation, scarring results, limiting regenerative capacity.<\/p>\n There is some evidence that evolution of the adaptive immune system is inversely correlated with regenerative capacity.3 <\/sup>Though the true link between these two evolved and devolved traits is not well understood, the shared trafficking mechanisms between immune cells and stem\/progenitor cells that contribute to regeneration may be a contributing factor and could in part, explain the inverse relationship between immune competence and robust regeneration.4<\/sup><\/p>\n While the addition of a highly specialised, adaptive immune system brings improved host defence against pathogens like viruses, bacteria, etc., some speculate that this defence function may come with a trade-off of full regenerative potential. In foetal development for example, the balance between immune competence and regeneration favours regeneration, a function largely lost in later life. Of note, this trade-off may provide for greater protection also against cancer development and metastasis, which involves many of the same mechanisms as immune trafficking required for robust regeneration.<\/p>\n Therapeutic approaches to stimulate regeneration should be cognisant of these trade-offs; nonetheless, important clues continue to be unveiled as our understanding of concomitant development of specialised immune function and regenerative capacity expands.<\/p>\n It is recognised that molecular signals originating in the extracellular matrix<\/a> (ECM) can modulate the seemingly mutually exclusive processes of immunity and tissue regeneration, although the specific bioactive molecules have yet to be identified.<\/p>\n The ECM is a rich source of signalling molecules for both the resident cells and cells that transit through the ECM in all tissues. These signals maintain a cell-friendly homeostatic microenvironment during states of health and mitigate the proinflammatory response and facilitate functional tissue reconstruction following injury. Isolation of the ECM from tissues such as dermis, small intestine, and urinary bladder, among others, by removal of cells (decellularisation) allows for the creation of ECM-based biomaterials. Such ECM-based materials are currently available as surgical meshes for ventral hernia repair, musculotendinous repair,5-9<\/sup> and dura mater replacement,10, 11<\/sup> among other therapeutic applications,12-15<\/sup> and as powders for topical wound care.16, 17<\/sup> These embedded signalling molecules are released during the process of ECM degradation in vivo. These signalling molecules favourably modulate the innate immune response and provide a microenvironment that influences cellular differentiation and spatial organisation.18-22<\/sup> The clinical outcome includes partial restoration of site appropriate normal tissue structure and function.<\/p>\n The concept of the microenvironment, and specifically the ECM, regulating cell and tissue morphogenesis is not new. Bissell and Sonnenschein have studied these concepts primarily in the context of cancer, focused upon the direct cell-matrix bi-directional crosstalk without mention of the indirect and paracrine influence of the immune system. Sonnenschein has referred to the temporal and spatial effects of the microenvironmnet upon cell behaviour as the tissue organisation field theory\u2019 (TOFT). 23, 25, 26, 27<\/sup><\/p>\n One example of a clinical application in which the ECM, when used as a biomaterial, can redirect dysregulated cell-signalling mechanisms involves its therapeutic use for the treatment of oesophageal adenocarcinoma.15<\/sup> Following full circumferential mucosal resection of the cancerous mucosa, an ECM bioscaffold was implanted in five patients. Patients achieved complete regeneration of a near-normal oesophageal mucosa and remained cancer free after a follow-up of more than five years. The use of this acellular regenerative medicine approach avoided the highly morbid procedure of esophagectomy, stricture (i.e. scar tissue) formation, and cancer progression. The restoration of normal or near normal tissue is an example of modulating the default tissue repair pathways toward activation of endogenous constructive and functional repair pathways by utilisation of Mother Nature\u2019s signals embedded within the ECM. This approach is a viable alternative to tissue engineering\/regenerative medicine approaches that involve cell-based therapy or exogenous tissue\/organ creation with subsequent surgical implantation.<\/p>\n A second clinical example of using naturally occurring signals to promote functional tissue restoration involves the use of ECM bioscaffolds for skeletal muscle repair. 13<\/sup> patients with volumetric muscle loss had exhausted all attempts to replace missing muscle tissue with conventional therapies.14<\/sup> Following implantation of a surgical mesh composed of ECM, the average patient showed a 37% increase in strength, 38% restoration of muscle mass, and greater the 250% improvement in ability to perform muscle functional activities. This cohort study followed extensive preclinical work in which ECM signalling molecules were shown to mitigate the proinflammatory immune response and promote the proliferation and differentiation of muscle progenitor cells.22, 28, 29<\/sup><\/p>\n The next generation of ECM-based therapeutics will undoubtedly involve the identification and use of various formulations of ECM, such as hydrogels that can be injected by minimally invasive methods, and the use of specific components of the ECM that are shown to possess immunomodulatory properties. An example of the latter is the recent identification of matrix bound nanovesicle\u2019s (MBV).30<\/sup> These nano-sized, lipid bound vesicles are firmly embedded within the structural components of the ECM and are a distinct subset of extracellular vesicles from the more commonly described exosomes found in body fluids.31<\/sup> MBV have potent immunomodulatory properties and are only released from their ECM microenvironment when the matrix is degraded, as occurs following tissue injury or during the degradation of an ECM biomaterial. The size and abundance of MBV provide great flexibility for therapeutic delivery and expansion of the use of naturally occurring signalling molecules to restore healthy tissue.32<\/sup><\/p>\n Advancements in surgical technique, 3D printing of tissues and organs, bioreactor technology, stem cell biology and related disciplines will clearly have a positive impact upon the clinical translation of regenerative medicine. It is just as evident that our understanding and ability to influence naturally occurring pathways of tissue development and regeneration through the use of ECM-based signals and related technologies will have a significant impact upon future therapeutic approaches.<\/p>\n Intellectual property related to the hydrogel form of extracellular matrix and matrix bound nanovesicles has been licensed to ECM Therapeutics, Inc., a company in which SFB, and JLD have a vested interest and hold officer positions.<\/p>\n Professor Stephen F Badylak<\/strong>Why did the evolution of Homo sapiens include the loss of regenerative capability and replacement by scar tissue formation?<\/h3>\n
Are there therapeutic strategies that compensate for loss of regenerative ability?<\/h3>\n
Regenerative Signals within ECM<\/h3>\n
Using the principles of Mother Nature to restore healthy tissue<\/h3>\n
References<\/h3>\n
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\nMcGowan Institute for Regenerative Medicine<\/strong>
\nUniversity of Pittsburgh<\/strong>
\nECM Therapeutics<\/strong>
\n118 Marshall Drive<\/strong>
\nWarrendale, PA 15086<\/strong>
\n+1 412 624-5308<\/strong>
\nbadysx@UPMC.EDU<\/strong><\/a>
\nTweet @McGowanRM<\/a><\/strong>
\nhttps:\/\/mirm-pitt.net<\/strong><\/a>
\nwww.ecmtherapeutics.com<\/strong><\/a><\/p>\nCo-author<\/h4>\n