Previously the donor to donor heterogeneity in MSCs has been

Previously, the donor-to-donor heterogeneity in MSCs has been revealed through significant differences in growth rate and clonogenic potential (Phinney et al., 1999). Such inter-subject variabilities (donor-to-donor) have been considered to be caused for the most part by factors imposed by long-term culture conditions (Bonab et al., 2006; Briquet et al., 2010; Pevsner-Fischer et al., 2011; Schallmoser et al., 2010; Lo Surdo and Bauer, 2012). However, intra-subject heterogeneity (hBMSC Otamixaban from the same donor) has also been recognized and in fact it was proposed that hBMSCs may actually exist in vivo as heterogeneous populations (Pevsner-Fischer et al., 2011; Phinney, 2007). For example, only a restricted population of MSCs has been shown to express neuroregulatory proteins (Crigler et al., 2006), or demonstrate selective in vivo tumor-homing properties (Bolontrade et al., 2012), or possess the capacity to express interleukin 1 receptor antagonist (Ortiz et al., 2007). Their plastic nature, the capacity to differentiate, and the complex stroma in the bone marrow favor hBMSCs to exist as heterogeneous subpopulations. In fact, such heterogeneity has a biological advantage in tissues, as it allows the selection of the appropriate cell type for various demanding conditions more so than a rigid and homogenous population (Pevsner-Fischer et al., 2011).
Summary
Author contributions STM — acquisition, analysis and interpretation of data, drafting the article and final approval of the version to be published; MR — acquisition, analysis and interpretation of data, revising the article and final approval of the version to be published; JLL — acquisition of data, revising the article and final approval of the version to be published; SRB — conception and design of the study, revising the article and final approval of the version to be published; MAA — conception and design of the study, analysis and interpretation of data, drafting and revising the article and final approval of the version to be published.
Acknowledgments This project was supported by the Modernizing Science Initiative funds provided by the Center for Biologics Evaluation and Research, US Food and Drug Administration. We appreciate critical reading of the manuscript by Syed Husain, Malcolm Moos, and Raj Puri.
Introduction Barth syndrome (BTHS, MIM# 302060) is a recessive disorder characterized by dilated cardiomyopathy, attended with skeletal myopathy, neutropenia, growth retardation and increased urinary excretion of 3-methylglutaconic acid in early childhood (Barth et al., 1983; Spencer et al., 2005; Takeda et al., 2011). The disease-causing gene was mapped to the TAZ1 locus in the q28 region of the X chromosome (Xq28) encoding for the mitochondrial protein tafazzin. Tafazzin is an evolutionary conserved CoA independent phospholipid acyltransferase, involved in remodeling of cardiolipin (CL), the hallmark lipid of mitochondria (Neuwald, 1997; Xu et al., 2006). CL is a constituent of the inner (75%) and outer (25%) membranes where it plays pleiotropic roles in the maintenance of membrane complexes and cristae morphology (Xu et al., 2005; Acehan et al., 2007; Gebert et al., 2009). After its synthesis CL is deacylated to monolysocardiolipin (MLCL) and subsequently reacylated by tafazzin. This remodeling process maintains the normal content and composition of cardiolipin in mitochondria. Although tafazzin is ubiquitously expressed in all human tissues, the remodeled molecular species of cardiolipin are cell-type and tissue specific. Heart and skeletal muscle, tissues that require high mitochondrial metabolic activity, contain mainly tetra-linoleoyl-CL ((C18:2)4-CL) in mitochondria whereas a broader species composition is found in other tissues, especially in the brain (Schlame et al., 2003; Schlame et al., 2002; Valianpour et al., 2002; Mckenzie et al., 2006; Houtkooper et al., 2009). It has been suggested that the different molecular species of cardiolipin observed in different cells and tissues are tailored to match the functional requirements and/or energetic demands of that cell or tissue (Houtkooper et al., 2009).