Abstract-Cardiac myocytes have been traditionally regarded as terminally differentiated cells that adapt to increased work and compensate for disease exclusively through hypertrophy. However, in the past few years, compelling evidence has accumulated suggesting that the heart has regenerative potential. Recent studies have even surmised the existence of resident cardiac stem cells, endothelial cells generating cardiomyocytes by cell contact or extracardiac progenitors for cardiomyocytes, but these findings are still controversial. We describe the isolation of undifferentiated cells that grow as self-adherent clusters (that we have termed "cardiospheres") from subcultures of postnatal atrial or ventricular human biopsy specimens and from murine hearts. These cells are clonogenic, express stem and endothelial progenitor cell antigens/markers, and appear to have the properties of adult cardiac stem cells. They are capable of long-term self-renewal and can differentiate in vitro and after ectopic (dorsal subcutaneous connective tissue) or orthotopic (myocardial infarction) transplantation in SCID beige mouse to yield the major specialized cell types of the heart: myocytes (ie, Key Words: adult stem cell Ⅲ myocardial regeneration and angiogenesis C ardiac myocytes have been traditionally regarded as terminally differentiated cells that adapt to increased work and compensate for disease exclusively through hypertrophy. 1 In the past few years, compelling evidence has accumulated suggesting that the heart has regenerative potential. [2][3][4][5] The origin and significance of the subpopulation of replicating myocytes are unknown; these issues could be relevant to understand the for mechanisms coaxing endogenous cardiomyocytes to reenter the cell cycle and to the search for strategies to transplant cardiac progenitor cells. 6 In fact, although embryonic stem cells have an exceptional capacity for proliferation and differentiation, potential immunogenic, arrhythmogenic, and, particularly, ethical considerations limit their current use. Moreover, autologous transplantation of skeletal myoblasts has been considered because of their high proliferative potential, their commitment to a well-differentiated myogenic lineage, their resistance to ischemia, and their origin, which overcomes ethical, immunological, and availability problems. However, even if phase II clinical trials with autologous skeletal myoblasts are ongoing, several problems related to potentially life-threatening arrhythmia (perhaps reflecting cellular uncoupling with host cardiomyocytes 7 ) must be taken into account when this approach is considered. Furthermore, although cardiomyocytes can be formed, at least ex vivo, from different adult stem cells, the ability of these cells to cross lineage boundaries is currently causing heated debate in the scientific community, 8 with the majority of reports indicating neoangiogenesis as the predominant in vivo effect of bone marrow or endothelial progenitor cells. 9,10 This report describes the identification and...

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During early pregnancy, uterine mucosa decidualization is accompanied by a drastic enrichment of CD56 high CD16 ؊ natural killer (NK) cells. Decidual NK (dNK) cells differ from peripheral blood NK (pbNK) cells in several ways, but their origin is still unclear. Our results demonstrate that chemokines present in the uterus can support pbNK cell migration through human endothelial and stromal decidual cells. Notably, we observed that pregnant women's pbNK cells are endowed with higher migratory ability compared with nonpregnant women's or male donors' pbNK cells. Moreover, NK cell migration through decidual stromal cells was increased when progesterone-cultured stromal cells were used as substrate, and this correlated with the ability of progesterone to up-regulate stromal cell chemokine expression. Furthermore, we demonstrate that dNK cells migrate through stromal cells using a distinct pattern of chemokines. Finally, we found that pbNK cells acquire a chemokine receptor pattern similar to that of dNK cells when they contact decidual stromal cells. Collectively these results strongly suggest that pbNK cell recruitment to the uterus contributes to the accumulation of NK cells during early pregnancy; that progesterone plays a crucial role in this event; and that pbNK cells undergo reprogramming of their chemokine receptor profile once exposed to uterine microenvironment. IntroductionNatural killer (NK) cells represent a distinct population of circulating and tissue-resident lymphocytes that play an important role in the early phases of immune responses against microbial pathogens by exhibiting cytotoxic functions and secreting a number of cytokines and chemokines. NK cells develop from a lymphoid precursor resident in the bone marrow (BM), considered the main site of NK cell generation, however, the existence of a pathway of NK cell development in the thymus has been recently suggested and evidence also indicates that final maturation of NK cell precursors can occur in the periphery. [1][2][3] During development and activation, NK cells acquire a multiple cell surface receptor system including both activating and inhibitory receptors that finely control their functional activation. 4 Some of these receptors are oligoclonally distributed and/or are expressed at different densities on circulating NK cells. Based on cell surface density of these receptors, phenotypically distinct peripheral blood NK (pbNK) cell populations have been identified and suggested to represent specialized subsets capable of performing different functions and endowed with distinct migratory properties. 5 Mature NK cells circulate mainly in the peripheral blood, but are also present in several lymphoid and nonlymphoid organs such as spleen, lymph nodes, tonsils, liver, lungs, intestine, and uterus. 1,[6][7][8] Interestingly, NK cells are the most abundant class of lymphocytes found in the mucosal tissues of maternal uterus where their number reaches 70% to 80% of the total leukocytes in the first trimester of pregnancy, then start to decline,...