Therapeutic use of adult cells with stem-or pro-genitor-like properties for cardiovascular disease remains controversial. Despite early preclinical claims of robust structural and functional recovery after myocardial infarction (MI), cell therapy trials for acute MI patients have been largely disappointing. 1 Focus has shifted to other indications such as chronic ischemic cardiomyopathy and heart failure, although again, efficacy remains controversial. 2, 3 Moreover, the mechanisms whereby cell therapy may impart benefits to a chronically infarcted heart with a stable scar remain unclear. We recently reported that intramyocardial injection of bone marrow mononuclear cells (MNCs), cardiacderived mesenchymal cells, nonviable cell debris, or noncellular inflammatory molecules all equivalently improved function of the acutely infarcted rodent heart via regional macrophage induction and border zone remodeling. 4 Since this rejuvenating response occurred during early infarct maturation (1 week after ischemia/reperfusion [I/R]), we also asked whether a similar effect would occur in a chronic stable scar long after resolution of acute wound healing. This is especially relevant because most clinical trials apply cell therapy many months or years after an MI. Thus, we attempted to nullify the hypothesis that cell therapy can revitalize hearts of mice with chronic scars (post-MI). Male and female C57BL/6J (wild type) mice were subjected to I/R injury via 120 minutes of coronary artery ligation. Eight weeks after I/R, animals were randomized to receive border zone intramyocardial injection of either 150 000 mTomato-labeled MNCs or sterile saline (Figure [A]). All procedures were conducted as previously described. 4 We first assessed retention of MNCs and resulting immune responses by histological analysis 3 days after intramyocardial injection. Small numbers of mTomato+ MNCs were observed in the infarct border zone, associated with greater CD68+-activated macrophage content versus saline controls (Figure [B and C]), indicating that MNCs induced acute inflammation around the stable scar. We next analyzed these mice after an additional 2 weeks by echocardiography and with histological methods. Here, we have reanalyzed and compared a previously published data set from our laboratory where mice received intramyocardial injections of 150 000 mTomato-labeled MNCs or sterile saline, but at 1 week post-I/R. 4 These 2 cohorts of mice were initiated concurrently with the same surgeon and experimental techniques. Mice that received cell therapy at 8 weeks post-I/R showed no improvement in contractile function as measured by fractional shortening (Figure [D]) or left ventricular remodeling as measured by end-systolic volume (Figure [E]). In contrast, intramyocardial injection at 1 week post-I/R attenuated left ventricular dysfunction and improved contractile performance (Figure [D and E] and in Vagnozzi et al4). Heart rates were equivalent across all groups (Figure [F]). We also assessed cardiac hypertrophy by gravimetric analysis (Figure [G]) and border zone fibrotic content (Figure [H]), and both were unchanged between MNC and saline treatments when delivered at 8 weeks post-I/R. We also analyzed deposition of cartilage oligomeric matrix protein (also known as thrombospondin-5) at the infarct border zone (Figure [I]). Cartilage oligomeric matrix protein is a matricellular protein highly expressed in chronic infarct scars, along with persistent accumulation of stably differentiated cardiac fibroblasts