Engineering Transferrable Microvascular Meshes for Subcutaneous Islet Transplantation
Song W, Chiu A, Wang LH, et al. Nat Commun. October 2019.
Cell transplantation is a promising therapeutic modality for diseases in which a cure can be achieved via the replacement of dysfunctional cells, such as islet transplantation for type 1 diabetes. However, clinical advances in this field have been hampered by the consistently observed poor vascularization of transplanted cells, particularly at a more clinically convenient site such as in the subcutaneous space.1 To overcome this obstacle, Song et al2 developed a micropillar-based “anchored self-assembly” of vascular endothelial cells to generate microvascular meshes for the purpose of subcutaneous islet transplantation with micropillars consisting of polydimethylsiloxane. Based on an arbitrary plan of micropillar placement, it has been possible to control the geometry and size of the generated microvascular meshes by providing specific guidance to the self-assembly of human umbilical vein endothelial cells (HUVECs) along the micropillars. In addition, anchoring points provided by the boundary micropillars may prevent the cellular structure from shrinkage during vessel maturation following in vivo implantation.
Using this approach, the authors show that (1) square meshes of up to 5 cm × 5 cm dimension can be readily fabricated using prearranged micropillars and HUVECs in the presence of fibrin; (2) subcutaneously implanted meshes fabricated as such promote vascular sprouting and efficient anastomoses between host and transplanted vasculatures; (3) boundary micropillars effectively prevent mesh shrinkage; (4) rat islets seeded on such microvascular meshes and transplanted in the subcutaneous space in diabetic severe combined immunodeficiency disease (SCID)-Beige mice consistently achieve superior vascularization and mesh-host vascular anastomoses compared to free transplant islets or islets transplanted on unstructured meshes without micropillars; moreover, superior glucose homeostasis in the diabetic SCID-Beige recipients had been achieved with this approach; (5) finally, human induced pluripotent stem-cell derived endothelial cells (iPSC-ECs) meshes can be fabricated in a similar fashion with precise geometry, dimension, and stability; indeed, rat islets transplanted on human iPSC-EC meshes in diabetic SCID-Beige mice exhibited similar implantation advantages as HUVEC meshes compared with islets on unstructured meshes or free islets. The ability to use iPSC-ECs to achieve effective vascularization provides additional potential for engineering patient-specific microvascular meshes.
The present study has thus provided a proof of principle of a new bioengineered platform for applications in cell transplantation. Follow-up studies determining the translational value of the new platform may include: (1) an assessment of host immunological responses to the micropillar meshes if implanted in immunocompetent instead of immunodeficient hosts; (2) the feasibility and utility of seeding additional immunomodulatory cells on the microvascular meshes; mesenchymal stem cells, for example, may enhance transplanted cell engraftment and/or function; (3) the applicability of this system in large animals such as pigs and nonhuman primates as an important intermediary step in its translation to human applications appears as a critical next step.
Nonetheless, the present study has provided a novel vascularized platform on which further engineering steps may be implemented for its ultimate clinical application as a subcutaneously implantable device for optimal cell transplantation.
Targeting the mTOR Pathway Uncouples the Efficacy and Toxicity of PD-1 Blockade in Renal Transplantation
Esfahani K, Al-Aubodah TA, Thebault P, et al. Nat Commun. October 2019.
Transplant recipients are prone to developing malignancies linked to immunosuppression. Immune checkpoint inhibitors (ICIs) have recently emerged as a class of effective anticancer drugs which work by enhancing host antitumor immunity. However, their use in transplant recipients remains controversial because of their putative and anecdotally reported effects on promoting a myriad of adverse events termed immune-related adverse events, the most troublesome of which is allograft rejection in such patients. Conversely, mammalian target of rapamycin (mTOR) inhibitors (mTORi) is known to both, modulate immune cell differentiation and function,1 in addition to tempering cancer cell proliferation and dissemination.2 Therefore, a theoretical advantage of combining ICI and mTORi in transplant recipients with cancers would be to promote simultaneous enhancement of anti-tumor immunity and inhibition of anti-donor alloimmunity. However, mechanistic studies supporting such a combination are lacking.
In the present study, Esfahani et al3 longitudinally examined an HLA-identical living-related kidney transplant recipient as she developed advanced-stage melanoma, underwent discontinuation of tacrolimus-based immunosuppression (wk 0), followed by initiation of ICI treatment (wk 2) and prompt precipitation of acute allograft rejection (wk 9); the transplant, however, was ultimately rescued by pulse steroids in combination with maintenance mTORi sirolimus as she continued with ICI treatment which led to tumor regression (wk 22).
Longitudinal phenotyping of peripheral blood mononuclear cells and serum cytokine production revealed: (1) ICI-precipitated allograft rejection is featured by significant activation and proliferation of peripheral CD4+ and CD8+ T cells, an intense eosinophilia, in addition to elevated serum levels of proinflammatory cytokines and chemokines. (2) The addition of mTORi to ICI, in conjunction with steroid treatment, effectively dampened T cell activation and proliferation, expanded regulatory T cells in circulation, and controlled inflammation. (3) Notably, the ICI-mTORi combination has been able to maintain the ongoing antitumor efficacy of ICI by facilitating interferon (IFN)-υ production by T cells reflected by elevated serum IFN-υ levels. Although an n = 1 experiment, this well-conducted study reveals several important implications on the use of mTORi in combination with ICI for cancer treatment in transplant recipients: (1) it is highly likely that preemptive initiation of mTORi in preparation of planned cessation of tacrolimus-based immunosuppression will prevent the precipitation of allograft rejection by ICI. This observation opens novel treatment possibilities that should now be formally tested and include a comparison of the current practice of using mTORi as a rescue therapy after allograft rejection; (2) while mTORi by itself does not seem to have a notable effect on clinical tumor regression, the possibility of a direct effect of mTORi on tumor cells when applied in combination with ICI should also be examined; (3) the individual as well as combined effects of ICI and mTORi on cellular metabolism and energy requirements influencing the process of T cell antigen recognition, cellular activation, expansion, and their differentiation into distinct functional subsets will need to be delineated in more detail.
1. Smink AM, de Haan BJ, Lakey JRT, et al. Polymer scaffolds for pancreatic islet transplantation - progress and challenges. Am J Transplant. 2018; 1892113–2119
2. Song W, Chiu A, Wang LH, et al. Engineering transferrable microvascular meshes for subcutaneous islet transplantation. Nat Commun. 2019; 1014602
1. Fantus D, Rogers NM, Grahammer F, et al. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat Rev Nephrol. 2016; 1210587–609
2. Luan FL, Hojo M, Maluccio M, et al. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation. 2002; 73101565–1572
3. Esfahani K, Al-Aubodah TA, Thebault P, et al. Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation. Nat Commun. 2019; 1014712