Title : Stem cell technologies to integrate biodesign-related tissue engineering within the frame of cell-based regenerative medicine: Towards the preventive, therapeutic and rehabilitative resources and benefits
Abstract:
Fundamental insights into cellular development, lineage commitment, and regenerative sig-nalling are driving innovations in therapy and design-driven tissue engineering. Stem Cell (SC) biology and applications examine the core mechanisms that regulate self-renewal, differentiation, and environmental responses of both embryonic and adult SCs. These insights enable to manipulate cell fate decisions for therapeutic purposes while ensuring safety and functional integration. The applications extend into disease modelling, drug discovery, and regenerative procedures, where SCs are used to generate tissue analogues or correct genetic anomalies. With increasing understanding of SC niches, SC biology and applications are tran-sitioning from experimental paradigms to clinical utility, offering viable solutions for neuro-degenerative, hematological, and cardiovascular disorders. Development of SC technology in combination with tissue engineering has opened new ways of producing engineered tissue substitutes.
The design of next-generation regenerative replacements either based on cellular or extra-cellular matrix technologies can address these shortcomings. For SC engineering, several techniques should be developed involving new materials and novel surface modifications of biomaterials; in addition, a deeper understanding of the interactions between cells and bio-materials will be needed. The continuous development of modern technology opens new insights of polymeric and smart material applications to enhance the SCs biological activity and their implementation by establishing a specific microenvironment mimicking natural cell niche and playing a key role in the maintenance of stemness and/or differentiation into mature specific lineages. Therefore, tissue engineered constructs and scaffolds could poten-tially become a promising alterative to the current therapeutic options for patients with the above-mentioned pathologies.
Of particular interest is an area of atherosclerotic complications and myocardial infarction, which are characterized by the irreversible loss of cardiac myocytes because of the ischemic necrosis. Therefore, the need to re-establish the structural and functional features of native heart tissue represents a major challenge for the field of cardiac regeneration and engineer-ing as the latest avenue to move ahead.
Cardiac Stem Cells (CTCs) are directly involved in cardiac cellular homeostasis during aging and adaptation to physiological and pathological stress and being transplanted into damaged hearts to generate de novo myocardial tissue. The niche for CSCs can be activated by several active biomolecules (including cytokines and growth factors), or through the injection of sys-temic drugs to obtain beneficial results similar to those of CSC transplantation.
Recent developments in SC-based tissue bioengineering and novel therapies offer promising options for restoring the functions of damaged heart and are now being investigated not only to protect the myocardium against ischemia-reperfusion injury but also regenerate the heart. The cardiac tissue regeneration with SCs, their exosomes or small vesicles may be effective therapeutic options. In this context, microRNA cargo within exosome-like vesicle transfer is considered to be an intriguing possibility to burst the cardiomyogenic potential of progenitor cells in the diseased heart. The future research and will be focused on the biology of the en-dogenous signalling pathways, and will lead the way for biodesign-driven applications of ex-osomes and small vesicles in precision cardiology practice. Upgraded knowledge and im-proved understanding of the interactions and signalling mechanisms between SCs and their niche or microenvironment within the in vivo setting, have improved the bioengineering ca-pabilities for optimal tuning of the SC microenvironment in vitro. Combining the cells with appropriate natural, synthetic, or decellularized scaffolds creates environments that better mimic the heart, resulting in improved outcomes. In this context, three-dimensional (3D) bioprinting is becoming a promising tissue engineering field that offers new opportunities to precisely place SCs within their niches layer-by-layer.
The crucial challenge is identification and selection of the most suitable SC type for cardiac regenerative medicine. Lessons from embryology offered important insights into the devel-opment of SC-derived mature Cardiac Myocytes (CMs). In this sense, SC therapy, such as po-tential use of human Mesenchymal Stem Cells (MSCs), Induced Pluripotent Stem Cells (IPSCs) and their exosomes will make it possible not only to address molecular mechanisms of car-diac conditioning, but also develop new therapies for ischemic heart disease.
The observation that CSCs can be developed inside a pool of immature cardiac cells by for-mation of “Cell-In-Cell Structures” (CICSs) has enabled us to conclude that CICSs being encap-sulated are implicated into mammalian cardiac myogenesis over the entire lifespan. The new CMs are generated through formation of CSC-derived Transitory Amplifying Cells (TACs) either in the CM colonies or in a process of intracellular development of CICSs being encap-sulated. The development of CSCs inside a population of mature CMs is resulting in the for-mation of pre-cardiac myocytes, which are able to substitute for irreversibly injured CMs, representing the major mechanism of myocardial regeneration. And that, in turn, would open up a green light to secure the targeted management of regenerative cardiac myogene-sis. Based on the new mechanisms and unique phenomenon, we are developing improve-ment strategies to boost the potency of SC repair and to generate the “next generation” of SC-based and regulatory biomolecules-based (bimodal) therapeutics.
The integration of gene editing technology and SC engineering in regenerative medicine has revolutionized CVD treatment by addressing genetic abnormalities and improving SC thera-pies via revolutionizing cardiovascular care by shifting from symptomatic to curative treat-ment, addressing the underlying mechanisms of disease. Future directions, including PPM-driven integration, immune modulation strategies, advancements in gene-editing technolo-gies, and design-inspired bioengineering synergy, offer a roadmap in SC treatment. The focus on SC therapy’s potential highlights its significant influence on cardiac medicine and points to a future in which individualized regenerative therapies will alleviate heart failures.
Given the complementary strengths of academic institutions and their skills in identification and validation of novel therapeutic targets, a collaborative approach between pharma and academia is essential to bring the exciting potential of regenerative therapeutics into a reali-ty and to encourage governments and companies to focus directly on regenerative medicine as a future potential economy and social insurance booster. We do hope that this viewpoint will illuminate key issues that currently limit synergistic relationships between pharma, bi-odesigners, clinicians and basic researchers and may even stimulate initiation of the multi-disciplinary collaborative projects.
Keywords: Personalized & precision medicine, stem cell, biodesign, tissue engineering, re-generative medicine
