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

Date Published: January 02, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Zhenzhen Wang, Chunming Wang, Ayipaxia Abudukeremu, Xiaying Rui, Shang Liu, Xiaoyi Zhang, Min Zhang, Junfeng Zhang, Lei Dong.


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.

Partial Text

Cell transplantation aimed at tissue reconstruction and regeneration holds promise to solve the fundamental challenges with organ transplantation, including an extreme shortage of whole organs suitable for medical implantation as well as its associated medical, social, and ethical issues.1, 2, 3 Ideally, the therapeutic cells are collected from the patient’s own tissue to avoid immunogenic rejection, expanded ex vivo and delivered back to the patient with or without the use of scaffolds (“autograft”).4, 5 However, the number of obtainable cells is usually far insufficient to construct a functional tissue or organ.3 One microliter of human tissue typically contains about 109 cells; and the liver, as an example of a whole organ, comprises over 1011 hepatocytes.6 It is unlikely to obtain extra billions of primary cells through isolation and ex vivo expansion because many somatic cells proliferate slowly or do not proliferate at all. This insufficiency is a long‐existing bottleneck hampering the clinical applications of cell transplantation. Besides, although theoretically stem cells have unlimited self‐renewal capacity and may provide more cells after expansion,7 their differentiation into desirable lineage and generation of functional tissues are hard to control.8 As such, cells that can rapidly proliferate and readily constitute a new tissue remain highly demanded in regenerative medicine.

One of the most exciting goals in regenerative medicine is to develop functional tissue/organs in the body using transplanted cells. To date, attempts towards this aim have been substantially hampered by several major obstacles, notably including the lack of sufficient cells suitable for transplantation and immune rejection against the “foreign” cells after transplantation.3, 43 In this study, we showed that xenogeneic cancer cells, delivered in an engineered matrix mimicking the TME, could successfully generate new functional tissues in vivo without being eliminated by the host immunity. These cells demonstrated an unparalleled (and underappreciated) potential in serving as a new, ample source of therapeutic cells for transplantation, while the TME‐mimetic niche played an indispensable role in supporting the survival and function of these cells.

Reagents: Agarose, gelatin, N,N′‐Carbonyldiimidazole (CDI), dimethyl sulfoxide (DMSO), STZ, and all other chemicals used in this study were purchased from Sigma‐Aldrich (St. Louis, MO, USA) unless otherwise stated. Interleukin‐4 (IL‐4) and bFGF were purchased from PeproTech (New Jersey, USA). Debrisoquine and 4‐hyroxydebrisoqune were obtained from Toronto Research Chemicals (TRC, Toronto, Canada).

The authors declare no conflict of interest.




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