Studies shed light on the mechanisms of corneal renewal and morbidity


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Can stem cells be identified and monitored in mature tissues? How can our organs cope with both the need for frequent tissue cell renewal and the need to protect the health of stem cells in tissues that are exposed to environmental hazards?

Collaboration between two research laboratories at the Technion Rappaport School of Medicine —The Israel Institute of Technology has recently donated a couple of innovative articles focused on the mechanisms of corneal renewal and morbidity, the transparent tissue that it is essential for vision and it serves as the “skin” of the eye. Similar to the skin, the cornea they come off constantly and are replaced by new cells originating from .

Unlike skin, clear cornea has no pigments that protect our skin. As such, it is highly exposed to harmful radiation. This is one of the reasons why they are located in the limbus, the narrow area between the transparent cornea and the opaque sclera (the white part of the eye). Many properties of these limbal stem cells (LSCs), such as prevalence, heterogeneity, and molecular signature, are unknown. This knowledge gap stops the development of LSC-based therapies to cure blindness. In addition, the issue of how stem cells face different physiological constraints is a key unanswered question in stem cell biology.

In the first article, published in Cell Stem cell, two previously unknown stem cell niches were discovered in the cornea. Each niche was found to contain unique stem cell populations that ensure its renewal. The second article, published in eLife, presents the sophisticated control mechanism that protects the cornea while maintaining a balance between cell death and personal tissue renewal. The article discusses how the basic properties of stem cells and differentiated cells affect the maintenance of stem cells in a remote and protected area and the rate of cell rotation, their ” freshness ”and aging. These advances, which emphasize the importance of interdisciplinary research, were achieved through collaboration between the research laboratory of Professor Ruby Shalom-Feuerstein, who specializes in stem cell research, and the laboratory of Professor Yonatan Savir. , specializing in quantitative biology and biophysics.

Trace and identify

The study published in Cell Stem cell was led by Dr. Anna Altshuler and Dr. Aya Amitai-Lange, from Professor Shalom-Feuerstein’s laboratory. They were integrated , including single-cell RNA sequencing and advanced clonal lineage tracing: identification of all “descendants” of a specific cell. The product is an unprecedented atlas describing the gene signature of limbal stem cells and their complete lineage.

The findings from this atlas show that the limbus houses two populations of stem cells located in two different niches that have not been previously described and that were coined ‘outer’ and ‘inner’ limbs. The inner limb contains a population of active LSCs, which divide frequently and routinely renew the cornea. The outer limbus contains a population of resting or inactive LSCs that divide more rarely, whose function is to protect the borders of the cornea and to serve as an emergency reservoir for stem cells awakened after an injury. Mathematical analysis of in vivo clonal growth dynamics suggested that LSC populations are abundant equipotent cells that follow stochastic rules that conform to neutral competition in niches that dictate their survival or extinction. Finally, the study also discovered a new function of immune system T cells that serve as external limbus cells and control the frequency of division and the healing process of external LSCs.

According to Professor Shalom-Feuerstein, “traditional dogma did not involve zoning or heterogeneity in the limbus, and regarded LSCs as rare cells that are surrounded by abundant short-lived progenitors. Hypothetical sparse entities were never found despite decades of limbo. This study proposes a new dogma that describes two discrete populations of LSC widespread in its niche and reveals its signature, dynamics, and function.We hope it paves the way for a better understanding of the involvement of LSC in blinding pathologies. corneal .. The LSC genetic signature atlas and niche components can translate into optimized LSC purification and growth in our culture dish which is currently quite limited. “

Between mortality and renewal

A key issue in stem cell biology is how stem cells can accurately balance cell loss and perfectly adjust tissue development and maintain its size and integrity. The second study, published in eLife and led by medical student Lior Strinkovsky and PhD. student Evgeny Havkin (both from the Savir lab), focused on this topic. The researchers developed a mathematical model that describes the dynamics of cell renewal in the cornea and tested several hypotheses and defined the control mechanism that creates a balance between cell renewal of corneal tissue and death of the cornea. aged cells.

The researchers evaluated different hypotheses that stem cells could maintain tissue homeostasis and tested their viability. The analysis revealed an inherent relationship between the lifespan of the corneal cell (the number of times they can divide) and the length at which cells affect each other as they replicate (a dividing cell competes only with the nearest neighboring cells or does it? affect a larger neighborhood?). One of the implications of these relationships is that “short-lived” progenitor cells that are thought to have a shelf life of 3-4 divisions may have a shelf life 10 to 20 times longer than previously thought. .

“Many of the tissues in our body (such as the cornea and skin) are in a perpetual state of death and cell renewal, and stem cells play a crucial role in the regenerative capacity of tissues,” he said. Professor Savir. “However, we still do not fully understand how stem cells control the ability to generate new cells so that the keep the right size. In addition, the lifespan of ordinary cells plays an important role in maintaining the balance between the number of new cells that are generated and the number of cells that die. Our work paves the way for hypotheses that can be easily tested experimentally. “

A new perspective on stem cells

The researchers believe their findings support the understanding that the traditional rare stem cell model is invalid. The findings of the present research are of great importance for understanding the basic properties of stem cells in different tissues such as skin, muscles, hair follicles, and bone marrow.

The researchers hope that the revelation of the identity and genetic signature of limbal stem cells in this study will pave the way for understanding the developmental processes of corneal disease and others, in which cells stem from various tissues are damaged, and will also lead to the development of innovative treatments and new technologies to repair damaged organs such as the cornea, among other things through the use of drugs aimed at the damaged genetic pathways of stem cells and their interaction with the supporting niche cells.

Structure of a stem cell niche

More information:
Anna Altshuler et al, Discrete limbic epithelial stem cell populations mediate corneal homeostasis and wound healing, Cell Stem cell (2021). DOI: 10.1016 / j.stem.2021.04.003

Lior Strinkovsky et al, Spatial correlations restrict cell life and pattern formation in corneal epithelial homeostasis, eLife (2021). DOI: 10.7554 / eLife.56404

Citation: Studies shed light on the mechanisms of corneal renewal and morbidity (2021, June 11) retrieved June 12, 2021 at html

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