BMP4-Generating Endothelial Cells Spur Regeneration of the Thymus

The research community is interested in regeneration and tissue engineering of the thymus, as this could in principle resolve one of the causes of age-related decline in immune system function. It is worth keeping an eye on present efforts, such as the one noted here, at an early stage of exploration. The thymus is where cells of the adaptive immune system mature, and is thus one of two important gating factors determining the pace at which new immune cells enter the body, ready for action. The other is the quality and activity of the hematopoietic stem cell population in the bone marrow, where immune cells are created.

The thymus is very active in childhood, but in early adulthood much of the specialized tissue - that hosts immune cells as they mature - atrophies to be replaced by fat. The remaining portion of that tissue fades away more slowly over a lifetime, and the pace at which new immune cells arrive fades with it. A sizable part of the failure of the immune system in later life derives from the ever slower pace at which immune cells are introduced. Malfunctioning, exhausted, and senescent immune cells accumulate. The immune system is eventually overwhelmed by the wear and tear of its duties, its component parts not replaced often enough. Restoring the active portions of the thymus to a youthful size has been shown to help in mice, and the hope is that it will do the same in humans.

The thymus, an organ in the lymphatic system, plays a critical role in immune function, producing the T cells essential to the immune response. The thymus, which gets smaller as we age, is highly sensitive to damage from stress and infection. And while it can recover from such insults - the process is known as endogenous thymic regeneration - more serious injury, for example, from chemotherapy or radiation, can extend recovery time considerably. That can result in an increased susceptibility to infections and even cancer relapse in patients while their T-cell count is low. "We don't really understand why the thymus shrinks as we get older, or how to make it bigger in patients where it would likely be helpful to have T cells be made."

That the thymus can regenerate itself has been known for nearly a century, but the mechanisms that control this process have not been widely studied. So researchers performed a transcriptome analysis of a section of the mouse thymus following damage from total body irradiation (TBI). They found a suite of genes that were significantly upregulated, including several already known to be involved in thymic function, as well as Bmp4. "We're really interested in understanding these processes of endogenous regeneration so that we may exploit them into clinically relevant and innovative strategies to boost thymic function."

The researchers treated mice with a BMP inhibitor starting one day before TBI to determine whether BMP signaling is necessary for endogenous regeneration. The treated mice had significantly worse recovery than controls, indicating BMP's importance in the process. In a related experiment, the researchers then injected endothelial cells into the bloodstreams of mice 72 hours after TBI, and found that doing so increased the number of thymic cells compared to controls. When they injected the cells directly into the thymus, 100-fold fewer endothelial cells were required to result in the same capacity for endogenous regeneration than when they injected them intravenously. This suggests that some endothelial cells from the bloodstream do make it to the thymus, they wrote in their report.

Therapies based on the research would be more likely to use isolated BMP4 than an endothelial cell line. Another future interesting direction would be whether this same pathway could be used in the aging thymus. In this scenario, or in damage associated with chronic conditions, perhaps boosting BMP4 activity would also drive thymic regeneration.



I wonder how far this is off an in human trial?

At what age would people start to benefit from Thymic Rejuvenation?

Posted by: Jim at January 16th, 2018 1:39 AM

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