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Review
. 2021 Dec 23;385(26):2451-2462.
doi: 10.1056/NEJMra1913421.

Immune and Genome Engineering as the Future of Transplantable Tissue

Jennifer Elisseeff  1 , Stephen F Badylak  1 , Jef D Boeke  1
Affiliations
Review

Immune and Genome Engineering as the Future of Transplantable Tissue

Jennifer Elisseeff et al. N Engl J Med. .
No abstract available

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Figures

Figure 1.
Figure 1.. Current and Future Strategies for Tissue Replacement.
Traditional-tissue engineering approaches (Panel A) seed cells onto a three-dimensional biomaterial scaffold that serves as a framework for new tissue development (i). The scaffold degrades as new extracellular matrix is secreted (ii), resulting in the desired functional tissue (iii). Tissue-engineered grafts (Panel B) can induce endogenous tissue development. Cells from donor tissue are seeded onto a scaffold (i), and mature tissue is produced in bioreactors (ii). Cells are removed (iii), leaving an extracellular matrix that can be readily stored and available when needed. After implantation (iv), cells migrate into the matrix and new tissue develops (v). Future strategies (Panel C) may use either allograft or xenograft tissue sources for transplantable, viable (living) organs or use an acellular tissue extracellular matrix from tissue to mobilize endogenous repair mechanisms.
Figure 2.
Figure 2.. Convergence of Tissue Transplantation and Repair.
Multiple immune cells contribute to tissue repair and transplant tolerance. T cells, highlighted here, contribute to both tissue repair and transplant tolerance through production of the immunosuppressive cytokines interleukin-10, transforming growth factor β (TGF-β), and interleukin-35 by regulatory T cells (Tregs) and in the context of a wound secrete growth factors specific to the tissue. Other T-cell types, such as type 2 helper T (Th2) cells, promote tissue repair through production of cytokines, including interleukin-4.
Figure 3.
Figure 3.. Phylogenetic Relationships among Mammalian Species Germane to Xenotransplantation.
The relationships among the mammalian species cited in this article are shown in this unrooted phylogenetic tree. The branches were formed with the use of an algorithm available at phyloT (https://phylot.biobyte.de) and visualized using iTOL (Interactive Tree of Life; https://itol.embl.de).
Figure 4.
Figure 4.. Xenotransplantation versus Exogenesis — Therapeutic Concepts.
Panel A shows xenotransplantation. (Human components are colored purple, and porcine components are colored green.) The genome of a pig is immunoengineered both by deleting porcine major antigens and by adding specific human transgenes expressing proteins that have been shown or hypothesized to improve the ability of “xeno organs” to persist (e.g., in animal models of xenotransplantation, such as nonhuman primates). Next, the result of the immunoengineering — a donor organism for xenotransplantation — produces an organ modified by immunoengineering. Here, the organ is a kidney, which is green because it has a mostly porcine genome but expresses certain human or humanized proteins (purple circles) intended to improve persistence in humans. Transplantation of the xeno kidney into the recipient restores function. Panel B shows exogenesis, in which a patient is the source of autologous human stem cells (e.g., patient-derived induced pluripotent stem cells [iPSCs]; purple cells). These are injected into a porcine blastocyst derived from a previously immune-engineered pig that has been “humanized” through the deletion of porcine genes and the introduction of human transgenes, as shown in Panel A. The exogenic blastocyst gives rise to a chimera producing a kidney that has a human genome, which can now be transplanted into a recipient.
See this image and copyright information in PMC

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