Welcome to the home page of Alexis Lomakin's lab at King's College
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,
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
underlying the dynamic cellular processes responsible for cell and
tissue morphogenesis in healthy and diseased state.
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
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 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:
- Be ambitious, persistent, and determined.
- Stay humble and modest. Individuals and teams can do amazing things when they share the credit.
- Great discoveries lurk everywhere; keep your eyes open.
- Success begins by choosing important problems, coming to fruition with great ideas and great execution.
- Stay focused and mindful of our goals with a clear understanding of the path ahead.
- Value uniqueness, helping people be the best they can be at what they do best.
- Work hard but have fun and be a little quirky.
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: firstname.lastname@example.org