A step towards clinical application of acellular matrix: A clue from macrophage polarization

Abstract

The outcome of tissue engineered organ transplants depends on the capacity of the biomaterial to promote a pro-healing response once implanted in vivo. Multiple studies, including ours, have demonstrated the possibility of using the extracellular matrix (ECM) of animal organs as platform for tissue engineering and more recently, discarded human organs have also been proposed as scaffold source. In contrast to artificial biomaterials, natural ECM has the advantage of undergoing continuous remodeling which allows adaptation to diverse conditions. It is known that natural matrices present diverse immune properties when compared to artificial biomaterials. However, how these properties compare between diseased and healthy ECM and artificial scaffolds has not yet been defined. To answer this question, we used decellularized renal ECM derived from WT mice and from mice affected by Alport Syndrome at different time-points of disease progression as a model of renal failure with extensive fibrosis. We characterized the morphology and composition of these ECMs and compared their in vitro effects on macrophage activation with that of synthetic scaffolds commonly used in the clinic (collagen type I and poly-L-(lactic) acid, PLLA). We showed that ECM derived from Alport kidneys differed in fibrous protein deposition and cytokine content when compared to ECM derived from WT kidneys. Yet, both WT and Alport renal ECM induced macrophage differentiation mainly towards a reparative (M2) phenotype, while artificial biomaterials towards an inflammatory (M1) phenotype. Anti-inflammatory properties of natural ECMs were lost when homogenized, hence three-dimensional structure of ECM seems crucial for generating an anti-inflammatory response. Together, these data support the notion that natural ECM, even if derived from diseased kidneys promote a M2 protolerogenic macrophage polarization, thus providing novel insights on the applicability of ECM obtained from discarded organs as ideal scaffold for tissue engineering.

Rethinking Regenerative Medicine From a Transplant Perspective (and Vice Versa)

“…Interestingly enough, natural ECM-based scaffolds obtained from human organs that are being used as supporting scaffolding material for bioengineered tissues, have been reported to contain significant amount of TGF-beta [127][128][129][130] and to be able to induce T-cell apoptosis and promote conversion of naïve CD4 + T cells into CD4 + CD25 + Foxp3 + Treg [118,129]. This observation is consistent with the evidence showing that the ECM possesses strong immunomodulatory properties.…”

“…Studies in rats showed that rabbit acellular decellularized muscle scaffolds down-regulated T cell xenogeneic responses and T H 1 effector function compared to fresh tissue by inducing a state of peripheral T cell hyporesponsiveness [131]. Moreover, ECM obtained from human normal or diseased organs, promote a protolerogenic macrophage polarization similar to the one that is observed in the adaptive regenerative healing response whereby a phenotypic transition from the pro-inflammatory M1 to the immune-modulating M2 phenotype occurs [128,132,133]. Therefore, combining the intrinsic ability of PSC-differentiated tissue to release TGF-beta with the immunomodulatory properties of ECMbased scaffolds, may represent a valuable strategy to reduce immunogenicity of bioengeneered organs.…”

A novel supercritical CO 2 -based decellularization method for maintaining scaffold hydration and mechanical properties

“…Once equilibrium was reached, the valve to the treatment chamber (7), which contained the porcine aorta (8), was opened, and CO 2 flow was programmed to 1 mL/min at the pump inlet. During treatment, the environmental chamber (4) (LU-113 model, ESPEC Corp., Osaka, Japan) was used to maintain the temperature at either 10 or 37°C, and a back-pressure regulator (11) (TESCOM, Elk River, MN) was used to keep the CO 2 pressure in the vessels constant at either 10.3 or 27.6 MPa (1500 or 4000 psi).…”

“…This is a particular strength of naturally-derived biomaterials, which have recently been shown to promote constructive remodeling during tissue growth [4,5]. Decellularized ECM has also been shown to elicit an anti-inflammatory immune response, which may be related to a reduced risk of rejection [6,7]. Decellularization is accomplished using a variety of techniques, including physical [8], chemical [9], and enzymatic treatment methods [10].…”

Regenerative immunology: the immunological reaction to biomaterials

“…Petrosyan et al . studied the effects of monocytes on different ECM in mice including acellular ECM scaffolds obtained from wild‐type kidneys as well as from kidneys of mice affected by Alport syndrome at different time points of disease progression. Results showed that both healthy and diseased ECM scaffolds induce differentiation of macrophages into reparative M2 macrophages, whereas artificial biomaterials favored differentiation into the M1 phenotype.…”