The Vascular Niche for Adult Cardiac Progenitor Cells

Figures

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  Figure 1. Examples of stem cell niches. (A) The acellular epithelial niche in Drosophila melanogaster. The ovary follicular cell compartment (FSC) is indicated with a yellow square; INT, integrins; α/β subunits; ECM, extracellular matrix; LANA, laminin A. Adapted from O’Reilly et al. (2008) [15]. The model is not conserved in mammals. (B) Simplified scheme for the bone marrow hematopoietic stem cell (HSC), composed of two subniches, the endosteal and the vascular niches. qHSC, quiescent hematopoietic stem cells; aHSC, activated hematopoietic stem cells; MSC, mesenchymal stem cells; MΦ, macrophages; MK, megakaryocytes; OB, osteoblasts; OC, osteoclasts; OM, osteomacs; CAR, CXCL12-abundant reticular cells.

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  Figure 2. Description of main candidate cardiac stem/progenitors [31,32,33,34,35,36,37,38,39,40,41].

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  Figure 3. Working model for the differentiation of B-CPC driven by ROS levels. (A) Genetic scheme of the mouse strain Bmi1Cre/+R26Rep/+ used for the characterization of B-CPC regulation/differentiation. Rep, indicates the use of YFP or Tmt as reporter; LoxP, specific LoxP sites for the Cre recombinase. (B) The B-CPC compartment is not in equilibrium with exogenous or endogenous precursors. B-CPC is a heterogeneous Sca1+ population with respect to Bmi1 expression levels. B-CPChigh correspond to the more immature and quiescent progenitors and most probably associate with a dedicated vascular niche (Niche A). It is proposed that later, ontogenically speaking, subpopulations B-CPCint/low and Sca1+Myh6+ cardiomyocyte (CM) committed progenitors could be associated with other pro-differentiation-biased niches (Niche B). In fact, it has been demonstrated that proliferative activated B-CPC are located more distantly with respect to the cardiac vessels. Progeny of B-CPC, 4-months after labeling is composed (relative to CM) by a 2.7 fold increase for smooth muscle cells (SMC) and 6.3-fold for endothelial cells (EC).

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  Figure 4. Oxidative stress is a driving force for homeostatic turnover in mouse heart. Total levels of reactive oxygen species (ROS) and regeneration capacity (turnover) are compared in mice aged 1 week old, 3 months old, and 1 year old. Levels of molecular damage (protein carbonyls and lipid peroxidation (malondialdehyde, MDA) were evaluated at those ages. Numbers (1 week) correspond to the levels (μM) of carbonyls and MDA; the surface of the indicated circles are proportional to the quantitative evaluation.

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  Figure 5. The vascular niche for cardiac B-CPC. Working model for the differentiation of B-CPC driven by ROS levels. The B-CPC are mainly confined to low-ROS perivascular spaces. They are regulated by modifications of ROS levels, cell–cell contacts, and secreted factors. B-CPC closer to the cardiac endothelium (EC), most in direct contact (B-CPChigh), are highly preferential in quiescence, show lower levels of total and mitochondria ROS, and are more protected against oxidative stress. The demonstrated EC/B-CPC pathways (Dll4⇒Notch) and (CXCR4/angiogenesis ⇐ CXCL12) are indicated. Gli1+ fibroblastic progenitors have also been mapped in the same niches. Those cell types that are supposed to be involved in vascular niche regulation but not yet confirmed are denoted by blue symbols. MΦ, macrophages; Neural, sympathetic neural fibers; Hemato, BM-derived cells. Mature cells: cardiomyocytes (CM), smooth muscle cells (SMC) and endothelial cells (EC).