Revisiting Whole Body Induced Cell Turnover as a Therapeutic Strategy

Last year some of the researchers associated with the Biogerontology Research Foundation proposed a class of therapy they call whole body induced cell turnover. I noticed a new paper and publicity materials on this topic today. In essence the goal is to augment the normal processes of cell turnover with therapies that remove and replace more cells than would normally be the case, thus clearing out the damage in those cells along the way. Since aging is caused by cell and tissue damage, in the ideal case this approach should act as a form of rejuvenation therapy. Obviously there are some limits here, such as areas of the brain where cells are storing the state of the mind, but in principle all other tissues are amenable to cell replacement. Beyond that, however, there is also the question of damage outside cells, such as waste compounds in tissue fluids and within the extracellular matrix structures that support cells. Further, consider signals propagated by damaged cells in one part of a tissue that affect normal cells elsewhere, such as the inflammation spurred by senescent cell signaling.

That said, it is nonetheless clear that the logical long-term direction for tissue engineering and regenerative medicine strategies must be to move towards more incremental, in-situ, small-scale replacement of damaged parts. Practical tissue engineering in the years immediately ahead will certainly start with tissue sections and organs grown in bioreactors and then transplanted into patients. Surgery is expensive and traumatic, however, and especially so in the old. In order to avoid those costs, all treatments will ultimately involve manipulation and repair of cell populations in the body, with the complexity baked into the therapeutics, and little human supervision of their progression required. This might be accomplished by delivery of signals, delivery of cells, or various other more sophisticated therapeutics, but there will be no surgery and no construction of tissue outside the body.

It is easy enough to point out the underpinnings of this trend, and theorize at the high level as to how to make it a reality, but the implementation details are of great importance - they are the whole of the story, in fact. Replacing cells in a way that is safe, and that also removes cellular damage rather than propagating it, isn't a straightforward task with an obvious solution, for all that there are plenty of starting points in today's biotechnology industry and research community. Strategies will likely vary considerably from tissue to tissue. It is likely that much more of the biochemistry of natural regenerative processes must be mapped and understood, so as to avoid interfering in counterproductive ways. Targeted cell destruction technologies must evolve into more sophisticated and discriminating forms. And so on. It is a big task and an expansive vision for the future of medicine.

Induced Cell Turnover: A proposed modality for in situ tissue regeneration and repair

Researchers originally proposed Induced Cell Turnover (ICT) in 2016. The proposed therapeutic modality would aim to coordinate the targeted ablation of endogenous cells with the administration of minimally-differentiated, hPSC-derived cells in a gradual and multi-phasic manner so as to extrinsically mediate the turnover and replacement of whole tissues and organs with stem-cell derived cells. In a new paper the authors refine the methodological underpinnings of the approach, take a closer look at potential complications and strategies for their deterrence, and analyze ICT in the context of regenerative medicine as an intervention for a broader range of conditions.

"One of the major hurdles limiting traditional cell therapies is low levels of engraftment and retention, which is caused in part by cells only being able to engraft at locations of existing cell loss, and by the fact that many of those vacancies have already become occupied by extracellular matrix (ECM) and fibroblasts (i.e. scar tissue) by the time the cells are administered, long after the actual occurrence of cell loss. The crux underlying ICT is to coordinate endogenous cell ablation (i.e. induced apoptosis) with replacement cell administration so as to manually vacate niches for new cells to engraft, coordinating these two events in space and time so as to minimize the ability for sites of cell loss to become occupied by ECM and fibroblasts. This would be done in a gradual manner so as to avoid acute tissue failure resulting from the transient absence of too many cells at any one time. While the notion of endogenous cell clearance prior to replacement cell administration has become routine for bone marrow transplants, it isn't really on the horizon of researchers and clinicians working with solid tissues, and this is something we'd like to change."

Cell-type and tissue-specific rates of induced turnover could be achieved using cell-type specific pro-apoptotic small molecule cocktails, peptide mimetics, and/or AAV-delivered suicide genes driven by cell-type specific promoters. Because these sites of ablation would still be "fresh" when replacement cells are administered, the presumption is that the patterns of ablation will make administered cells more likely to engraft where they should, in freshly vacated niches where the signals promoting cell migration and engraftment are still active. By varying the dose of cell-type targeted ablative agents, cell type and tissue-specific rates of induced turnover could be achieved, allowing for the rate and spatial distribution of turnover to be tuned to the size of the tissue in order to avoid ablating too many cells at once and inadvertently inducing acute tissue failure.

"ICT could theoretically enable the controlled turnover and rejuvenation of aged tissues. The technique is particularly applicable to tissues that are not amenable to growth ex vivo and implantation (as with solid organs) -- such as the vascular, lymphatic, and nervous systems. The method relies upon targeted ablation of old, damaged and/or senescent cells, coupled with a titrated replacement with patient-derived semi-differentiated stem and progenitor cells. By gradually replacing the old cells with new cells, entire tissues can be replaced in situ. The body naturally turns over tissues, but not all tissues and perhaps not optimally."

Induced Cell Turnover: A novel therapeutic modality for in situ tissue regeneration

Induced Cell Turnover (ICT) is a theoretical intervention in which the targeted ablation of damaged, diseased and/or nonfunctional cells is coupled with replacement by partially differentiated induced pluripotent stem cells in a gradual and multi-phasic manner. Tissue-specific ablation can be achieved using pro-apoptotic small molecule cocktails, peptide mimetics, and/or tissue-tropic AAV-delivered suicide genes driven by cell-type specific promoters. Replenishment with new cells can be mediated by systemic administration of cells engineered for homing, robustness, and even enhanced function and disease resistance. Otherwise, the controlled release of cells can be achieved using implanted biodegradable scaffolds, hydrogels, and polymer matrices. In theory, ICT would enable in situ tissue regeneration without the need for surgical transplantation of organs produced ex vivo, and addresses non-transplantable tissues (such as the vasculature, lymph nodes, skin and nervous system). We have outlined several complimentary strategies for overcoming barriers to ICT in an effort to stimulate further research at this promising interface of cell therapy, tissue engineering, and regenerative medicine.

Comments

I've thought about this exact therapy in combination with stem cell replacement to deal with Van Vijg's favourite "limiting factor to human lifespan" - loss of tissue homogeneity.

Posted by: Anonymoose at June 15th, 2017 6:50 PM

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