The molecular logic of tissue quality control: a perspective on the utility of time

When tissues detect defective cells, they face a dilemma: whether to help repair (cell homeostasis) or decide to eliminate them (cell death). The same quandary occur at sub-cellular levels too: when cells sense a defect within, they face the difficult choice of either resolving the defect or sacrificing themselves altogether. Decades of work helped reveal cellular mechanisms of homeostasis (e.g., ISR, UPR, DDR, and on) and death (apoptosis, ferroptosis, cell extrusion, and on), yet the molecular justification and decision-making mechanisms that help choose between these two functionally conflicting phenomena are slowly being unearthed. Conflicting indeed, as while the former choice helps a cell survive, the latter benefits the tissue at large by containing the defect locally to avoid its spread. In rarer occasions, even at the face of extreme stressors and damages, cells don’t display hallmarks of death and continue to live on (e.g. polyploidy or suspended animation). How could cells decide between these vital choices?

We rationalize that, at least in part, time is of the essence. When a cellular damage arises, how long could the cell or tissue persist by repairing it? How does a cell decide to slow, speed up or arrest itself to resolve the damages? Does this choice differ when in the cell or tissue’s life cycle the damage occurs? For instance, does it matter that the damage occurs in rapidly dividing cells in a developing tissue versus in post-mitotic cells in an adult organ? Does it make a difference that the same type of damage occurs at different phases of the cell’s division cycle? When and how does a cell or tissue switch from repairing the damages to committing death? Does the cell or tissue age make a difference in the choice of homeostasis versus death? Or, how quickly to go from the former to the latter? All these questions boil down to decision-making mechanisms that rely on measuring the duration of damages or on monitoring the timing and amplitude of their consequences. As such, we conjecture that unravelling the molecular mechanisms and logic of time control in tissue quality maintanence promises the next-generation therapeutic approaches to treating tissue malformations, damages and disorders.

Embryo development as an experimental paradigm for cell homeostasis and elimination: Our lab’s goals and long-term interests on tissue quality control

A hallmark of proper embryogenesis is the homeostatic ability to repair or eliminate defective cells that emerge spontaneously in early development. Defects in this homeostasis are considered primary causes of congenital anomalies and fertility decline. Classic studies using model organisms (e.g. flies and mice) revealed that experimental perturbations to genome integrity can exacerbate the incidents of such defective cells and their elimination during early embryogenesis. Since a loss of DNA-damage checkpoint complexes (e.g., ATR/Chk1) similarly increase defective cells, this has led to a conventional view that embryonic quality control centers on genomic insults and their eliminations.

Paradoxically, however, other studies have demonstrated that Chk2-/- flies and mice (deficient of the checkpoint complex that help eliminate such defective cells) are viable and display normal homeostasis during development. This has suggested that most endogenous defects are likely handled by repair mechanisms, making cell elimination non-essential unless homeostasis fails. Yet, our understanding of what such homeostatic repair mechanisms are, and how they coordinate with cell elimination mechanisms, remains mostly conceptual. Thus, deciphering the molecular logic of how early embryos cope with endogenous defects will pave the way towards an informed physiological framework for reproductive medicine.

Research direction #1: How do cells anticipate the onset, and measure the duration, of diverse stressors that threaten embryonic quality?

Embryonic development in animals unfolds mostly on a programmed set of maternal and zygotic events that give rise to tissues and organs. As such, embryos are expected to experience time-dependent stressors depending on the stage of development. For instance, the cleavage division stage of embryogenesis faces challenges associated with nucleotide metabolism and DNA replication given the speed of the cell cycles. Similarly, the consumption of maternal deposits could induce a time-dependent starvation stress. The same anticipatory logic could be applied to a cell’s own division cycle in which it is expected to experience, e.g., transcription based stresses during interphase or mesoscale chromosome damages during mitosis. As such, our lab is interested understanding the molecular mechanisms that enable cells to anticipate the onset and measure the duration of various stressors that threaten cellular and developmental quality.

Research direction #2: What is the molecular logic and genetic landscape of embryonic quality control?

Besides anticipated developmental stressors, embryonic cells can experience unexpected exogenous (e.g. irradiation) or stochastic endogenous defects (e.g. fluctuations in protein folding success). What are the molecular mechanisms that help cells decide between maintaining homeostasis versus eliminating themselves? If the former is chosen, when does the cell turn from homeostasis to death mechanisms? These decisions are especially important during development, given its time restrictions due to ever progressing endogenous programs of proliferation and differentiation. In this regard, whether and how do these decisions converge on cellular and developmental time control mechanisms to pace the system (i.e., to slow down, speed up, arrest the development)? By attempting to chart its genetic landscape, we aspire to address the molecular logic of embryonic quality control.

Research direction #3: What are the pathological consequences of early failures in cell homeostasis or elimination on developmental success and adult physiology?

Finally, we are interested in understanding how a failure of cell homeostasis or elimination in early embryogenesis could influence the overall outcome of developmental progression and/or the overall physiology of the adult animals.