Life-Long KGF Overexpression Produces a Very Much Larger Thymus in Aged Mice

In today's open access paper, researchers map out the various epithelial progenitor cell populations responsible for producing and then maintaining the thymus, finding that these cells are quite diverse, with several types participating at different times during development and adult life. The thymus is of great interest in the context of aging because (a) it is where thymocytes mature into T cells of the adaptive immune system, and (b) it atrophies with age, active tissue replaced by fat, and the supply of new T cells greatly diminished. This is one of the major contributions to the age-related decline of the immune system. A better understanding of how the thymus is maintained could lead to novel approaches to regeneration, and maintenance of immune competence into later life.

Numerous efforts have been made to identify a viable approach to regrow the thymus in adult humans. One of these is delivery of fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF). A good number of studies demonstrate that this approach can provoke regrowth of the adult thymus in animals. Today's paper adds to this body of knowledge by showing that life-long overexpression of KGF in genetically engineered mice produces a thymus that remains large into later life, and does so without exhausting the progenitor cell populations responsible for maintaining this tissue. Unfortunately the side-effects of KGF make it impossible to deliver large enough doses systemically in humans to produce the same outcome. A clinical trial in HIV patients failed for this reason. Direct injection of the thymus would work to put enough KGF in the right place, but it is likely only palatable to regulators in cases of severe illness, given the small risk of serious harm that accompanies deep organ injection, particularly in older people.

Secrets of thymus formation revealed

Rsearchers have now succeeded in describing the unexpected diversity of thymic epithelial cells at the transcriptional level. Algorithms developed for the precise description of differences in the gene activity of individual cells made it possible to identify potential precursor cells. As a result, for the first time it became possible to study the development of thymic epithelium at different ages in equisite molecular detail. This kind of analysis is of particular interest to immunologists because the thymus is subject to significant changes during life. Rapid organ growth and massive T-cell production are characteristic of the early developmental stages. In contrast, there is a gradual loss of functional thymic epithelial cells in old age and, therefore, decreased T-cell production. These age-related changes are associated with a reduced immune function.

The researchers identified two bipotent progenitor populations of the thymic epithelium in their analysis. An "early" progenitor population takes over the primary role in the thymus formation during embryonic development. While in the juvenile organism, a subsequent "postnatal" progenitor population significantly determines the continued thymus formation in adulthood.

Developmental dynamics of two bipotent thymic epithelial progenitor types

T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells (TECs) and diminished naive T cell production with age. Here we combine scRNA-seq and a new CRISPR-Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium.

We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without transgenicexhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity. Mice treated with pharmacological doses of the Fgfr2b ligand KGF, the human homologue of Fgf7, exhibit an increase in the number of TECs. However, it is not known whether Fgf stimulation targets progenitors, mature TECs, or both. To examine this question, we generated several mouse models for continuous autocrine provision of an Fgfr2b ligand in the thymus. We established that, under physiological conditions, the extent of Fgf signalling in TECs is determined by limiting levels of ligands, rather than the receptor; notably, we found that pharmacological supplementation of the Fgfr2b ligand Fgf7 could be mimicked in vivo by ectopic expression of Fgf7 in the TECs of transgenic mice. Continuous autocrine provision of Fgf7 within the epithelial compartment in this transgenic model increased the number of TECs and thymocytes and resulted in a massive and sustained increase in thymus size.


rKGF is already an approved drug under the tradename Kepivance (US) so this is quite interesting.

Posted by: Chris at June 6th, 2022 11:39 PM
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