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.
Highlights
Cell transplantation aimed at tissue reconcancer cells (XCC) may be an alternative source of therapeutic cells, but their transplantation risks both immune rejection and unwanted spreading
We assumed that Tumor Homogenate (TH) contained the essential ingredients to modulate the stromal cells into a pro-tumor phenotype which would favor the growth of transplanted cells and creation of tumor microenvironment (TME)-like microenvironment
Schematic diagram of the concept that an engineered TME-mimetic niche formed by active soluble factors in tumor extract (TH), basic fibroblast growth factor, and injectable hydrogel facilitates the xenogeneic cancer cells (XCC) to develop into a functional tissue in immunocompetent mice
Summary
Cell transplantation aimed at tissue reconcancer cells (XCC) may be an alternative source of therapeutic cells, but their transplantation risks both immune rejection and unwanted spreading. We aimed to use xenogeneic cancer cells (XCC) and create an immunosuppressive microenvironment (an “enclave”) for these trans-species cells to grow Their migration out of this niche would be naturally inhibited by the robust cross-species immune response. It is common to create tumor models in cancer research by transplanting xenogeneic (human) cancer cells into immunocompromised mice—but not immunocompetent mice, where promptly triggered immunogenic rejection and could immediately eliminate the transplanted cells.[15] Likewise, this mechanism could be utilized to confine the implanted XCC in the engineered immunogenic enclave. Cultivating and transplanting XCC in an engineered, TME-mimetic matrix niche would exert the maximum potency of cancer cells for tissue regeneration while preventing their spreading in the host body The tumor is recognized as “foreign” by the immune system but can effectively escape immunosurveillance to flourish.[16–19] The key reason is the formation of its unique microenvironment, in which multiple biochemical and physical signals dynamically coordinate to educate immunocytes, including macrophages, dendritic cells (DCs) and lymphocytes—which continue infiltrating into the tumor as the blood vessels invade—into an immunosuppressive phenotype.[20–23] The educated immune cells, in turn, help the tumor escape immune attack, promote neoplasm growth, encourage angiogenesis, and thereby shape TME into a better platform to support cancer cell growth.[24,25] cultivating and transplanting XCC in an engineered, TME-mimetic matrix niche would exert the maximum potency of cancer cells for tissue regeneration while preventing their spreading in the host body
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