Abstract
Very little is known about the mechanisms that contribute to organ size differences between species. In the present study, we used a mouse model of embryonic pig tissue implantation to define the role of host Factor VIII in controlling the final size attained by the implant. We show here that pig embryonic spleen, pancreas, and liver all grow to an increased size in mice that are deficient in the Factor VIII clotting cascade. Similar results were obtained using the transplantation model after treatment with the low molecular weight heparin derivative Clexane which markedly enhanced transplant size. Likewise, enhanced size was found upon treatment with the direct thrombin inhibitor Dabigatran, suggesting that organ size regulation might be mediated by thrombin, downstream of Factor VIII. Considering that thrombin was shown to mediate various functions unrelated to blood clotting, either directly by cleavage of protease-activated receptors (PARs) or indirectly by cleaving osteopontin (OPN) on stroma cells, the role of PAR1 and PAR4 antagonists as well as treatment with cleaved form of OPN (tcOPN) were tested. While the former was not found to have an impact on overgrowth of embryonic pig spleen implants, marked reduction of size was noted upon treatment with the (tcOPN). Collectively, our surprising set of observations suggests that factors of the coagulation cascade have a novel role in organ size control.
Highlights
Despite great progress in the molecular dissection of embryogenesis, the mechanisms controlling the size of tissues and organs remain a mystery
Implantation of Pig Embryonic Tissues We have previously shown that implantation of pig embryonic spleen precursor tissue can correct hemophilia in factor VIII KO NOD-SCID mice by providing the necessary Factor VIII[11]
We observed that the size of the implanted spleen of these hemophilic mice was significantly larger compared to that growing in non-hemophilic control mice
Summary
Despite great progress in the molecular dissection of embryogenesis, the mechanisms controlling the size of tissues and organs remain a mystery. It is thought that extrinsic control mechanisms are associated with nutrition or systemic growth signaling factors, such as those operating through the insulin/ PI3K or the TOR pathways, while intrinsic mechanisms are likely linked to patterning morphogens and apoptosis-signaling complexes, as well as to stem cell numbers[1,2,3,4]. When multiple fetal mouse thymus glands were transplanted into an adult mouse, each was found to grow to its normal adult size[6]. When the same experiment was performed using fetal spleens, the total mass of the transplanted spleen tissue attained the mass of only a single normal adult spleen, suggesting that the growth of these fetal tissues is limited by extrinsic factors, outside the spleen[7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
