Engineering a Tumor Microenvironment‐Mimetic Niche for Tissue Regeneration with Xenogeneic Cancer Cells

Abstract

The insufficient number of cells suitable for transplantation is a long‐standing problem to cell‐based therapies aimed at tissue regeneration. Xenogeneic cancer cells (XCC) may be an alternative source of therapeutic cells, but their transplantation risks both immune rejection and unwanted spreading. In this study, a strategy to facilitate XCC transplantation is reported and their spreading in vivo is confined by constructing an engineering matrix that mimics the characteristics of tumor microenvironment. The data show that this matrix, a tumor homogenate‐containing hydrogel (THAG), successfully creates an immunosuppressive enclave after transplantation into immunocompetent mice. XCC of different species and tissue origins seeded into THAG survive well, integrated with the host and developed the intrinsic morphology of the native tissue, without being eliminated or spreading out of the enclave. Most strikingly, immortalized human hepatocyte cells and rat β‐cells loaded into THAG exert the physiological functions of the human liver and rat pancreas islets, respectively, in the mouse body. This study demonstrates a novel and feasible approach to harness the unique features of tumor development for tissue transplantation and regenerative medicine.

Growing Trans‐Species Islets in Tumor Extract‐Remodeled Testicles

“…To achieve this goal, we first remodeled one testicle by injecting a soluble extract from the tumor homogenate (TH), which we previously showed could protect the implanted xenogeneic cancer cells (XCCs) from rejection in immunocompetent mice . Then, we transplanted either rat insulinoma beta cells (INS‐1 cells, known for their higher proliferation rate) or primary rat islet cells into the TH‐remodeled mouse testicle and examined their long‐term survival, response to glucose, and insulin‐producing functions in the host body . The results validated our hypothesis that the TH‐remodeled testicle provided an enhanced immunosuppressive microenvironment to support the growth of xenografted islets, which exerted prolonged antidiabetic function and minimized graft rejection.…”

“…In comparison, our strategy aims to address this issue fundamentally by changing an existing organ of the body—the testicle—into an immunotolerant environment for transplantation. We learned from previous studies (and then validated in this study) that remodeling of the testicle is necessary . Accordingly, we utilized the TH to change the inner structure and physiological features of the mouse testicle with the aim of enhancing and prolonging its immunosuppressive characteristics.…”

“…Our strategy has also taken into account the safety issue throughout the design and implementation of the experiments. First, we rigorously examined in this and previous studies that although TH efficiently modulates the local immune response in the testicle, it has little influence on the global immune system . Next, despite their cancerous nature, INS‐1 cells displayed a normal islet‐like morphology and the expected insulin‐producing activity, without showing any abnormity.…”

“…Extracts from TH : The tumor homogenate was obtained according to the method reported in the published literature . Briefly, to generate the heterotopic tumor model, mouse sarcoma cell line S180 cells (1 × 10 6 ) were injected subcutaneously into the left arm pits of the animals.…”

“…In this study, as shown in the Scheme , we propose to remodel the testicle in mice for the growth of trans‐species (rat) islet cells. To achieve this goal, we first remodeled one testicle by injecting a soluble extract from the tumor homogenate (TH), which we previously showed could protect the implanted xenogeneic cancer cells (XCCs) from rejection in immunocompetent mice . Then, we transplanted either rat insulinoma beta cells (INS‐1 cells, known for their higher proliferation rate) or primary rat islet cells into the TH‐remodeled mouse testicle and examined their long‐term survival, response to glucose, and insulin‐producing functions in the host body .…”