Humanized mouse model for assessing the human immune response to xenogeneic and allogeneic decellularized biomaterials

Abstract

Current assessment of biomaterial biocompatibility is typically implemented in wild type rodent models. Unfortunately, different characteristics of the immune systems in rodents versus humans limit the capability of these models to mimic the human immune response to naturally derived biomaterials. Here we investigated the utility of humanized mice as an improved model for testing naturally derived biomaterials. Two injectable hydrogels derived from decellularized porcine or human cadaveric myocardium were compared. Three days and one week after subcutaneous injection, the hydrogels were analyzed for early and mid-phase immune responses, respectively. Immune cells in the humanized mouse model, particularly T-helper cells, responded distinctly between the xenogeneic and allogeneic biomaterials. The allogeneic extracellular matrix derived hydrogels elicited significantly reduced total, human specific, and CD4+ T-helper cell infiltration in humanized mice compared to xenogeneic extracellular matrix hydrogels, which was not recapitulated in wild type mice. T-helper cells, in response to the allogeneic hydrogel material, were also less polarized towards a pro-remodeling Th2 phenotype compared to xenogeneic extracellular matrix hydrogels in humanized mice. In both models, both biomaterials induced the infiltration of macrophages polarized towards a M2 phenotype and T-helper cells polarized towards a Th-2 phenotype. In conclusion, these studies showed the importance of testing naturally derived biomaterials in immune competent animals and the potential of utilizing this humanized mouse model for further studying human immune cell responses in an in vivo environment.

Decellularized Extracellular Matrix Materials for Cardiac Repair and Regeneration

“…While dECM materials may not be inflammatory, the response with each new therapeutic material and device must be thoroughly evaluated. To allow for evaluation of human immune response without clinical treatment of patients, Wang et al developed a humanized mouse model for improved testing of naturally derived biomaterial immune responses and compared injectable porcine or human cECM therapy using the mouse model . Three weeks after injection, the allogenic matrix reduced total T helper cell infiltration compared to xenogeneic ECM, which was not observed in wild‐type mice.…”

Injectable Hydrogel-Based Nanocomposites for Cardiovascular Diseases

“…Compared to natural hydrogels, synthetic hydrogels perform a strong mechanical properties and a possibility of being linked to new functional groups by physical and chemical means to achieve the desired function (Highley et al, 2016;Pena et al, 2018). Besides, extensively alternative synthetic materials range and the low risk of immune rejection implanted in the body (Wang R. M. et al, 2017) also facilitates the development of synthetic hydrogels. However, synthetic hydrogels are encountered with low adhesion, due to the lack of cell attachment sites, and poor biocompatibility (Do et al, 2015).…”

Limitations of recellularized biological scaffolds for human transplantation

“…Despite providing insight into whether a protein or chemical can lead to an immune response, the immune system among species is quite different, especially between mice and humans. This confounds translation of animal findings to humans (Mestas & Hughes, ; R. M. Wang et al, ). To overcome this problem, larger animal models closer to humans, including nonhuman primates and pigs, are being explored (Sakai et al, ; Stahl et al, ).…”

“…The use of an acellular scaffold is based on the premise that any immune response should be minimal, thereby avoiding the need for immunosuppressant therapy. However, the evaluation process of most published studies only spans a few weeks to a few months (Fishman et al, ; Lange et al, ; Liu et al, ; Maughan et al, ; Mirmalek‐Sani et al, ; Wang, Johnson, et al, ). This raises the concern of monitoring a minimal immune response without considering a potential graft failure occurring later.…”

“…Fishman et al, 2013;Lange et al, 2017;Liu et al, 2017;Maughan et al, 2017;Mirmalek-Sani et al, 2013;Wang, Johnson, et al, 2017).…”