Systems Biology of Cell & Tissue Morphogenesis (sBCTM)

Welcome to the home page of Alexis Lomakin's lab at King's College London:

The Lomakin Lab addresses basic, curiosity-driven, questions in cell biology concerning spatiotemporal organization of cells that make up tissues and organs in the human body. How do cells sense their own shape and size, and measure distances? How do cells adapt their dimensions to variations in the extracellular environment? How do cells use information about their geometry to localize signaling or make decisions? How do cells estimate dimensions of the organ or tissue that they build?

To answer these questions, the lab utilizes an interdisciplinary approach combining molecular and cellular biology with bioengineering, physicochemical biology, and computational modeling. Collaborating with physicists and engineers, we develop creative experimental approaches to manipulate, image, and quantify cellular processes in living cells and reconstituted tissues. With this approach, we wish to discover quantitative molecular and biomechanical mechanisms underlying the dynamic cellular processes responsible for cell and tissue morphogenesis in healthy and diseased state.

Our vision:

It is our conviction that we need more curiosity-driven basic research aimed at understanding the principles governing life. The reasons are simple: 1) we need to learn more about the world around us; and 2) a robust and diverse basic research enterprise will bring innovative ideas and approaches essential for developing new medicines and improving the lives of humankind (an interesting essay on this matter is published here: Mol Biol Cell. 2015 Nov 1; 26(21): 3690-3691).

Stem cells - the new "model organism":

As cell biologists, we have often had an uneasy relationship with translational research. Many of our studies are in model organisms or animal cell lines, and considerable time is needed before discoveries in these models can be transformed into know-how solutions for pharma, biotech, and medical sectors. Working in human stem cells (SCs) allows cell biologists to investigate fundamental mechanisms, secure in the knowledge that their discoveries can be rapidly translated into understanding and managing human health and disease (more thoughts on this topic can be found here: Mol Biol Cell. 2017 Jun 1; 28(11): 1409-1411).

Our lab has a long-standing interest in the phenotypic plasticity of somatic epithelial cells and their progenitors (Nat Cell Biol. 2015 Nov; 17(11): 1435-1445). Isolated from adult human tissues, somatic epithelial SCs display a remarkable capacity to generate self-assembling organ-like structures out of one single cell. Nowhere is this better illustrated than in epithelial SCs of the skin. Human epidermal SCs represent highly proliferative multipotent SCs that have the potential to reconstitute in vitro the formation of rapidly renewing, multilayered epithelial cell sheets that persist as a histologically normal epidermis upon autologous transplantation. The regeneration and homeostatic maintenance of the epidermis in or out of the human body is governed by a tunable balance between epidermal SC proliferation and differentiation (Nat Cell Biol. 2016 Feb; 18(2): 145-156). This balance allows the tissue to reach and dynamically sustain its stereotypic size and shape in the face of fluctuating environment. Extreme imbalances in epidermal SC proliferation and differentiation are associated with aging and poor wound healing (excessive differentiation), and hyperproliferative disorders and cancers (excessive proliferation). In order to develop ways to correct these imbalances, we have to first of all understand (1) how epidermal SCs switch from proliferative activity to quiescence and differentiation, and (2) how the cells are able to maintain their distinct functional regimes over time. Trying to answer these questions, we base our work on a conceptual ground: Self-organizing systems studied in physics and social sciences exhibit feedbacks and a high degree of connectivity. These characteristic traits have increasingly become accepted as a ubiquitous signature of biological systems, and human epidermis with its constituent cells is no exception.

Cross-disciplinary research into epithelial stem cell biology - phase transitions in-and-out of epidermal keratinocytes:

(1) Considering that the switch of epidermal keratinocytes from proliferation to differentiation is known to be reversible under certain conditions, it is unlikely that genetic determinism is the only factor that controls cell fate decision-making in the epidermis. Moreover, the commitment of epidermal SCs to their differentiation program is not an abrupt process and consists of consecutive transitions between intermediate cell states, suggesting that cells in the epidermis may function more like variable rheostats, rather than two-state switches. To do so, the cells must coordinate their autonomous programs with local and global changes at the cell population level. Our research objective is to understand how this coordination is achieved. It is proposed that proliferation of epidermal stem/progenitor cells increases cell population density. Above a critical density threshold, the tissue converts into a jammed, solid-like state. This phase transition is due to increased pressure that cells exert on each other in the conditions of cellular crowding (Nat Cell Biol. 2018 Jan;20(1):69-80). The latter in turn triggers competition among cells for the occupancy of the limited substrate area. Winner cells are more likely to preserve their "stemness", while loser cells with a weakened grip for the extracellular matrix are destined to differentiate and delaminate to locally and transiently relief lateral cell-on-cell pressure and to build an upper differentiated epidermal cell layer. In the absence of this cell density feedback, cell differentiation and delamination rates are significantly decreased. At the same time, local tissue fluidization during epidermal wounding, when a fraction of the cell population is lost and the crowding effect is locally relieved, upregulates cell proliferation rates (Nat Cell Biol. 2016 Feb; 18(2): 145-156). How do keratinocytes sense the phase transitions in the epidermis to adjust their behaviors? Do they measure the forces in the tissue? Do keratinocytes count the number of cells in the population? Do the cells size-up the amount of the extracellular matrix available for attachment? And if so, do they have built-in rulers to perform these functions? Interestingly, epidermal keratinocytes change their size in response to cell shape deformations that they experience in the crowded/uncrowded epidermis. At the same time, keratinocytes are known to differentiate only when they reach a certain size (J Cell Biol. 1981 Sep 1; 90(3): 738-742). How do keratinocytes know when they are the right size? Can they use this information during tissue building and homeostatic maintenance? Answering all these questions keeps us busy in the lab.

(2) Comparative mechanophenotyping of individual epidermal SCs vs. differentiated keratinocytes shows that epidermal cell differentiation is associated with cell solidification (Nat Cell Biol. 2018 Jan;20(1):69-80). At the same time, recent evidence suggests that when yeast and bacterial cells become dormant under certain conditions, they undergo solidification to resemble a glass-like material (Cell. 2014 Jan 16; 156(0): 183-194 and eLife. 2016; 5: e09376). This in turn feeds back to metabolic and proliferative activity of the cells, which points to the intriguing possibility that a similar physico-chemical feedback might operate in epidermal keratinocytes. Considering that cell transitions from a fluid-like to a more solid-like state are reversible, this generic mechanism can serve for "locking" cells in a dormant state, yet allowing them to regain activity when necessary. We are currently testing this exciting hypothesis by comparing various biophysical properties of differentiated human keratinocytes vs. their undifferentiated progenitors.

Our collaborators: 

Our main collaborators for the human keratinocyte project are the lab of Fiona Watt at the Centre for Stem Cells & Regenerative Medicine, King's College London.

Our long-term ambitions:

Our long-term ambition is to discover the universal morphogenetic code that directs cell behaviors and tissue building in the skin epithelium and to translate this knowledge into innovative approaches to boosting "stemness" of epidermal keratinocytes to ultimately be able to repair and rejuvenate adult human skin. To this end, we have begun establishing links with industrial partners, such as the Skin Stem Cells Research Group at L'Oréal Paris: 

Our values and culture:

Job opportunities:

Our vision is to solve complex biological problems in cell & tissue research through highly collaborative, international, and multi-disciplinary team science. Therefore, we welcome scholars from all over the world with backgrounds in both the biomedical and physical/computational sciences. If you are interested in opportunities within the Lomakin lab, please e-mail Dr. Alexis Lomakin: alexis.lomakin@kcl.ac.uk