Revisiting the matricellular concept

•The matricellular protein family includes new members.•Matricellular proteins function in blood, ECM, cell surface, and intracellularly.•Matricellular proteins directly and indirectly regulate diverse cellular functions.•Matricellular proteins act via receptors, growth factors, soluble or ECM molecules.•Matricellular proteins are therapeutic targets in disease and regenerative medicine.

The concept of a matricellular protein was first proposed by Paul Bornstein in the mid-1990s to account for the non-lethal phenotypes of mice with inactivated genes encoding thrombospondin-1, tenascin-C, or SPARC. It was also recognized that these extracellular matrix proteins were primarily counter or de-adhesive. This review reappraises the matricellular concept after nearly two decades of continuous investigation. The expanded matricellular family as well as the diverse and often unexpected functions, cellular location, and interacting partners/receptors of matricellular proteins are considered. Development of therapeutic strategies that target matricellular proteins are discussed in the context of pathology and regenerative medicine.