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In human heart failure and in murine hearts with left-ventricular pressure overload (LVPO), increases in fibrosis are associated with increases in myocardial stiffness. Secreted protein acidic and rich in cysteine (SPARC) is shown to be necessary for both cardiac fibrosis and increases in myocardial stiffness in response to LVPO; however, cellular sources of cardiac SPARC are incompletely defined. Irradiation and bone marrow transfer were undertaken to test the hypothesis that SPARC expression by bone marrow-derived cells is an important mediator of fibrosis in LVPO. In recipient SPARC-null mice transplanted with donor wild-type (WT) bone marrow and subjected to LVPO, levels of fibrosis similar to that of WT mice were found despite the lack of SPARC expression by resident cells. In recipient WT mice with donor SPARC-null bone marrow, significantly less fibrosis versus that of WT mice was found despite the expression of SPARC by resident cells. Increases in myocardial stiffness followed a similar pattern to that of collagen deposition. Myocardial macrophages were significantly reduced in SPARC-null mice with LVPO versus that of WT mice. Recipient SPARC-null mice transplanted with donor WT bone marrow exhibited an increase in cardiac macrophages versus that of SPARC-null LVPO and donor WT mice with recipient SPARC-null bone marrow. Expression of vascular cellular adhesion molecule (VCAM), a previously identified binding partner of SPARC, was assessed in all groups and with the exception of WT mice, increases in VCAM immunoreactivity with LVPO were observed. However, no differences in VCAM expression between bone marrow transplant groups were noted. In conclusion, SPARC expression by bone marrow-derived cells was critical for fibrotic deposition of collagen and influenced the expansion of myocardial macrophages in response to LVPO. NEW & NOTEWORTHY Myocardial fibrosis and the resultant increases in LV and myocardial stiffness represent pivotal consequences of chronic pressure overload (PO). In this study, a murine model of cardiac fibrosis induced by PO was used to demonstrate a critical function of SPARC in bone marrow-derived cells that drives cardiac fibrosis and increases in cardiac macrophages.

Matricellular proteins are secreted proteins that, among other functions, can contribute to extracellular matrix (ECM) assembly including modulation of cell:ECM interactions. Recent discoveries have indicated a fundamental role for the ECM in the regulation of inflammatory responses including cell extravasation and recruitment, immune cell differentiation, polarization, activation, and retention in tissues. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular collagen-binding protein implicated in fibrillar collagen assembly in the ECM of connective tissue as well as in basal lamina organization. Functions of SPARC in modulating cell adhesion events are also reported. Studies of phenotypic responses observed in SPARC-null mice to a variety of injury models have yielded interesting insight into the functional importance of SPARC production and aberrations in ECM structure that occur in the absence of SPARC that influence immune cell behavior and inflammatory pathways. In this review, we will discuss several examples from different tissues in which SPARC-null mice exhibited an inflammatory response distinct from those of SPARC expressing mice and provide insight into novel ECM-dependent mechanisms that influence these responses. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.