Increasing donor age adversely impacts beneficial effects of bone marrow but not smooth muscle myocardial cell therapy

Abstract

We evaluated the impact of donor age on the efficacy of myocardial cellular therapy for ischemic cardiomyopathy. Characteristics of smooth muscle cells (SMC), bone marrow stromal cells (MSCs), and skeletal muscle cells (SKMCs) from young, adult, and old rats were compared in vitro. Three weeks after coronary ligation, 3.5 million SMCs (n = 11) or MSCs (n = 9) from old syngenic rats or culture medium (n = 6) were injected into the ischemic region. Five weeks after implantation, cardiac function was assessed by echocardiography and the Langendorff apparatus. In the in vitro study, the numbers and proliferation of MSCs from fresh bone marrow and SKMCs from fresh tissue but not SMCs were markedly diminished in old animals (P < 0.05 both groups). SKMCs from old animals did not reach confluence. After treatment with 5-azacytidine (azacitidine), the myogenic potential of old MSCs was decreased compared with young MSCs. In the in vivo study, both SMC and MSC transplantation induced significant angiogenesis compared with media injections (P < 0.05 both groups). Transplantation of SMCs but not MSCs prevented scar thinning (P = 0.03) and improved ejection fraction and fractional shortening (P < 0.05). Load-independent indices of cardiac function in a Langendorff preparation confirmed improved function in the aged SMC group (P = 0.01) but not in the MSC group compared with the control group. In conclusion, donor age adversely impacts the efficacy of cellular therapy for myocardial regeneration and is cell-type dependent. SMCs from old donors retain their ability to improve cardiac function after implantation into ischemic myocardium.

Isolation, characterization and differentiation of mesenchymal stem cells from amniotic fluid, umbilical cord blood and Wharton's jelly in the horse

“…A negative correlation between donor age, number and proliferative capacity of MSCs isolated from young and old donors has been demonstrated by several authors (Martin et al 1970, Schneider & Mitsui 1976, Majors et al 1997, D'Ippolito et al 1999, Stenderup et al 2003, Mareschi et al 2006, but widely different results have been obtained with regard to MSC antigen expression. Recently, Stolzing et al (2008) confirmed those already demonstrated in previous studies (D 'Ippolito et al 1999, Mendes et al 2002, Chen et al 2005, Zhang et al 2005, Zheng et al 2007, Kretlow et al 2008, observing a significant age-related change in membrane markers expression levels, an alkaline phosphatase activity, chondrogenic and myogenic differentiation potency decline with donor age in contrast with adipogenic differentiation. However, these data are in contrast with those reported by other research groups (Bergman et al 1996, Stenderup et al 2001, Bellows et al 2003, which showed no age-related differences in differentiation potency.…”

Efficacy and Safety of Intracoronary Autologous Bone Marrow‐Derived Cell Transplantation in Patients With Acute Myocardial Infarction: Insights From Randomized Controlled Trials With 12 or More Months Follow‐Up

“…31 Moreover, transplantation of BMC from aged rats did not improve heart function after MI. 32 Subgroup analysis based on the study by Cao also suggested that younger patients might benefit more from BMC infusion than older patients. 19 In the second instance,more significant LVEF improvementwas observed when BMC were administered 6 or 7 days after acute MI compared to 5 days after acute MI.…”

Small Molecule Mesengenic Induction of Human Induced Pluripotent Stem Cells to Generate Mesenchymal Stem/Stromal Cells

“…Perinatal sources seem attractive, with greater frequency and higher proliferative-potential MSCs, but a major limitation is that MSCs can typically only be isolated from around one-third of umbilical cord blood specimens [1,2]. Earlier fetal, placental, and amniotic sources yield abundant primitive MSCs with greater differentiative ability than later sources [5,6], but they require invasive procedures and/or access to abortal tissue, with its attendant ethical issues. There is thus a major unmet need for new sources of MSCs for clinical application.…”