Title : The promising future of the unique translational tool to manage cardiac self-renewal and regeneration to secure the post-infarction period
Abstract:
The approaches securing cardiac regeneration in post-infarction period are not available to be practiced. The key problem is the identity of cells be born to generate functionally active cardiac myocytes replenishing those being lost during ischemia. With identification of resident Cardiac Stem Cells (CSCs), it has been supposed that the latter may be a crucial source to initiate and prompt myocardial self-renewal and regeneration.
In the last years, the focus has been moved towards a concept of the new wave of Cardiac Myocyte (CM) formation via a scenario of dedifferentiation and proliferation of mature CMs. The observation that CSCs can be developed inside a pool of immature cardiac cells by formation of “Cell-In-Cell Structures” (CICSs) has enabled us to conclude that CICSs being encapsulated are implicated into mammalian cardiac myogenesis over the entire lifespan. It had been demonstrated before that 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 encapsulated.
The analysis of adult rat cardiac cell suspension 1-5, 10, and 14 days after permanent coronary occlusion and ischemia/reperfusion has gifted a researcher a unique phenomenon of TAC release from mature CMs with clear sarcomeric structure. In this case a development of the intracellular CSC occurs within the vacuole pre-formed by CSC-driven sarcolemma-induced invagination. The comparison of TACs exiting the CICS with capsule with TACs just released from non-encapsulated CICS showed that non-encapsulated CICS-derived TACs are characterized by increased expression of cardiac markers and decreased expression of stemness-related markers. Those data for the first time suggest that the development of CSCs inside the encapsulated CICSs is important for cardiac self-renewal and maintenance of CSC-based pool. At the same time, the development of CSCs inside a population of mature CMs is resulting in the formation 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 myogenesis.
SC therapies are viable alternatives to conventional treatments with substantial therapeutic potential and market opportunities. And the lessons learned from our studies would yield fundamental biological insights in the repair of ischemic and other myocardial diseases whilst securing the therapeutic resources with the unique future.
Meanwhile, translational research & applications are keeping success in the field elusive in terms of return on investment and in terms of attractiveness to investors within and outside of biopharma and clinical market as well. The SC market itself is predicted to grow to around $12.1 billion by 2024, whilst the development of the SC therapy into further applications has not yet become common practice, and the true potential of regenerative medicine has yet to be demonstrated fully. For instance, the allogeneic or ‘off-the-shelf’ business model for SC-based therapies is far more akin to current biopharmaceuticals, where the product maintains long-term stability.
Moving forward, we must better characterize SC-based therapy and clinical trials, facilitating decision making across the sector. More basic science investigation is required to elucidate the specific mechanism(s) by which SC promote cardiac regeneration and/or repair, and how cells can be optimally delivered and engineered. As our understanding of SC therapy increases, it becomes more likely that clinical trials can produce truly meaningful results with implications for clinical practice.
Based on the new mechanisms and unique phenomenon, we are developing improvement strategies to boost the potency of SC repair and to generate the “next generation” of SC-based and regulatory biomolecules-based (bimodal) therapeutics. Moreover, our strategies should aim at more personalized SC therapies in which individual disease parameters influence the selection of optimal cell type, dosage and delivery approach. And encouraging pre-clinical and clinical studies as one and solid entity reporting significant SC-mediated cardiac regeneration would rapidly pave the way for clinical translation. So, a desire to discover innovative SC-based technologies of the next-step generation would encourage governments and companies to focus directly on regenerative medicine as a future potential economy and social insurance booster.
Thus, prospective research should focus on the development of specific responder scores and the identification of prognostic SC- and cardiac damage-related biomarkers to identify patient cohorts who benefit most from distinct SC treatments. Thereby, a higher standardization of study designs and the establishment of a global open-access database for the registration and publication of pre-clinical and clinical trials would greatly improve the comparability and access of obtained data. The worldwide SC therapy market is still in an early stage. And the developing translational pipelines for rising applications will build the competition among merchants amid the conjecture time fram
