Abstract
The major goal of regenerative medicine is to repair damaged tissues and organ systems, thereby restoring their native functions in the host. Control of innervation by re-grown or implanted structures, and integration of the nascent nerves into behavioral/cognitive programs of the host, remains a critical barrier. In the case of sensory organs, this is particularly true, as afferent neurons must form connections with the host to communicate auditory, visual, and tactile information. Xenopus embryos and tadpoles are powerful models for such studies, as grafting techniques allow for the creation of eyes and other sensory structures along the body axis, and the behavior of the resulting organism can be quantitatively analyzed. Previous work has demonstrated that ectopic eyes could be grafted in blinded tadpoles, allowing some of the animals to learn in a simple light-preference assay. Here, we show that it is possible to improve the efficiency of the process in the context of a novel image-forming vision assay, using a drug already approved for human use. Innervation of the host by ectopic eyes can be increased by targeting a serotonergic signaling mechanism: grafts treated with a 5-HT1B/D agonist strongly innervate the recipient compared with untreated grafts, without large-scale disruption of the host nervous system. Blind animals possessing eye grafts with the augmented innervation demonstrate increased performance over untreated siblings in wavelength-based learning assays. Furthermore, treated animals also exhibit enhanced visual pattern recognition, suggesting that the increased innervation in response to 5-HT1B/D activation leads to enhanced functional integration of the ectopic organ with the host central nervous system and behavioral programs. These data establish a model system and reveal a new roadmap using small molecule neurotransmitter drugs to augment innervation, integration, and function of transplanted heterologous organs in regenerative medicine.
Highlights
The future of regenerative medicine will surely involve the transplantation of a wide variety of bioengineered structures, from hybrid artificial constructs to stem cell-derived organoids grown in vitro
5-HT1B/D activation induces innervation of transplanted tissue following eye graft in Xenopus embryos this hypothesis, we examined the anatomy of another sensory system, the host’s lateral line, in the presence or absence of 5HT1B/D activation
When grafted animals were reared in the 5-HT1B/D activator Zolmitriptan, 40% of the transplants innervated the host, with afferent innervation present in the ventral fin and trunk of the tadpoles
Summary
The future of regenerative medicine will surely involve the transplantation of a wide variety of bioengineered structures, from hybrid artificial constructs to stem cell-derived organoids grown in vitro. We mine if any of ectopic neurites were present in the brain of the have been testing strategies for inducing innervation of ectopic structures, focusing on bioelectric properties of the host and the neurotransmitter molecules downstream of voltage-dependent signaling.[22,23,24,25] Here, we demonstrate that strong innervation can be induced for eye grafts by exposure to a 5-HT1B/D agonist, without significantly altering elements of the host CNS This induced innervation, causing animals receiving treated grafts to perform significantly better in wavelength-discrimination tasks than animals receiving untreated grafts. We show that the function of ectopic eyes in otherwise blind animals is for light sensing, but to confer performance in a novel behavior assay that requires image-forming vision (pattern detection) Taken together, these data demonstrate that organ grafts are capable of providing sensory information to a vertebrate host, host.
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