Decellularized extracellular matrix mediates tissue construction and regeneration

Abstract

Contributing to organ formation and tissue regeneration, extracellular matrix (ECM) constituents provide tissue with three-dimensional (3D) structural integrity and cellular-function regulation. Containing the crucial traits of the cellular microenvironment, ECM substitutes mediate cell-matrix interactions to prompt stem-cell proliferation and differentiation for 3D organoid construction in vitro or tissue regeneration in vivo. However, these ECMs are often applied generically and have yet to be extensively developed for specific cell types in 3D cultures. Cultured cells also produce rich ECM, particularly stromal cells. Cellular ECM improves 3D culture development in vitro and tissue remodeling during wound healing after implantation into the host as well. Gaining better insight into ECM derived from either tissue or cells that regulate 3D tissue reconstruction or organ regeneration helps us to select, produce, and implant the most suitable ECM and thus promote 3D organoid culture and tissue remodeling for in vivo regeneration. Overall, the decellularization methodologies and tissue/cell-derived ECM as scaffolds or cellular-growth supplements used in cell propagation and differentiation for 3D tissue culture in vitro are discussed. Moreover, current preclinical applications by which ECM components modulate the wound-healing process are reviewed.

Keywords: 3D culture; decellularized extracellular matrix; organoids; tissue repair.

Fig. 1

Role and composition of stem-cell niche. The stem-cell niches retain the stemness of adult stem cells in a quiescent state. When tissue is injured, the surrounding microenvironment actively signals stem cells to promote either self-renewal or differentiation to form new tissues. The niches include cell–matrix, cell–protein, protein–matrix, cell–cell interactions, hypoxia, and metabolism. Among these niche factors, cell–matrix interactions play a key role in prompting cell adhesion, migration, proliferation, and differentiation for tissue regeneration. The matrix regulates stem-cell behavior through structural supports, biochemical signaling, growth factor induction, and biomechanical regulation during tissue repair.

Fig. 2

Cell-seeded decellularized small intestine submucosa scaffolds. (A) Masson trichrome staining of canine bone marrow stromal stem cells (red) seeded on SIS scaffolds (blue). (B) Immunohistochemistry staining of α-smooth muscle actin of bone marrow stromal cells (Brown). The photomicrograph of cell-seeded SIS scaffolds is adapted from BJU International [168] with permission.

Fig. 3

Bone marrow stromal cells-seeded decellularized extracellular matrix promoted in vivo bladder tissue regeneration. Both autologous bone marrow stromal cells-seeded (A) and bladder cells-seeded SIS scaffolds (B) expressed α-smooth muscle actin 10 weeks after transplantation in a canine model following partial cystectomy, assessed by immunohistochemistry staining. The images are adapted from BJU International [168] with permission.

Fig. 4

Hippo signaling pathway YAP/TAZ for regulating cell behaviors and tissue regeneration. The Hippo pathway is regulated by an intracellular network relaying a multitude of external inputs. Mechanical stress and cell-extracellular matrix (ECM) adhesion changes can regulate the Hippo pathway through integrin signaling. Activation of the Hippo pathway is associated with the phosphorylation of the core Hippo pathway kinases, including mammal Ste20-like kinase 1 (MST1) and MST2, Salvador 1 (SAV1), MOB1A and MOB1B, large tumor suppressor kinase 1 (LATS1) and LATS2, the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ), which leads to proteasomal degradation. Conversely, when the Hippo kinase cascade is not activated, unphosphorylated YAP/TAZ binding with TEAD transcription factor can activate specific genes, regulating ECM remodeling, cellular behaviors (cell attachment, proliferation, migration, and differentiation) and tissue regeneration.