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Journal ArticleDOI

Mesenchymal stem cells as trophic mediators.

01 Aug 2006-Journal of Cellular Biochemistry (Wiley-Blackwell)-Vol. 98, Iss: 5, pp 1076-1084
TL;DR: Several studies which tested the use of MSCs in models of infarct (injured heart), stroke (brain), or meniscus regeneration models are reviewed within the context of M SC‐mediated trophic effects in tissue repair.
Abstract: Adult marrow-derived Mesenchymal Stem Cells (MSCs) are capable of dividing and their progeny are further capable of differentiating into one of several mesenchymal phenotypes such as osteoblasts, chondrocytes, myocytes, marrow stromal cells, tendon-ligament fibroblasts, and adipocytes. In addition, these MSCs secrete a variety of cytokines and growth factors that have both paracrine and autocrine activities. These secreted bioactive factors suppress the local immune system, inhibit fibrosis (scar formation) and apoptosis, enhance angiogenesis, and stimulate mitosis and differentiation of tissue-intrinsic reparative or stem cells. These effects, which are referred to as trophic effects, are distinct from the direct differentiation of MSCs into repair tissue. Several studies which tested the use of MSCs in models of infarct (injured heart), stroke (brain), or meniscus regeneration models are reviewed within the context of MSC-mediated trophic effects in tissue repair.

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Citations
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Journal ArticleDOI
TL;DR: Current understanding of the cellular and molecular mechanisms of fibrogenesis is explored and components of the renin–angiotensin–aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs.
Abstract: Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.

3,390 citations


Cites background from "Mesenchymal stem cells as trophic m..."

  • ...Stem cell therapies have already proved successful at restoring cardiac function in injured hearts [173], therefore they might prove successful for a wide variety of fibroproliferative disorders....

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Journal ArticleDOI
TL;DR: The potential paracrine mechanisms involved in adult stem cell signaling and therapy are reviewed: cytokines and growth factors can induce cytoprotection and neovascularization, and cardiac remodeling, contractility, and metabolism may also be influenced in aParacrine fashion.
Abstract: Animal and preliminary human studies of adult cell therapy following acute myocardial infarction have shown an overall improvement of cardiac function. Myocardial and vascular regeneration have been initially proposed as mechanisms of stem cell action. However, in many cases, the frequency of stem cell engraftment and the number of newly generated cardiomyocytes and vascular cells, either by transdifferentiation or cell fusion, appear too low to explain the significant cardiac improvement described. Accordingly, we and others have advanced an alternative hypothesis: the transplanted stem cells release soluble factors that, acting in a paracrine fashion, contribute to cardiac repair and regeneration. Indeed, cytokines and growth factors can induce cytoprotection and neovascularization. It has also been postulated that paracrine factors may mediate endogenous regeneration via activation of resident cardiac stem cells. Furthermore, cardiac remodeling, contractility, and metabolism may also be influenced in a paracrine fashion. This article reviews the potential paracrine mechanisms involved in adult stem cell signaling and therapy.

1,855 citations

Journal ArticleDOI
TL;DR: The novel role of exosomes highlights a new perspective into intercellular mediation of tissue injury and repair, and engenders novel approaches to the development of biologics for tissue repair.

1,816 citations


Cites background from "Mesenchymal stem cells as trophic m..."

  • ...In support of this paracrine hypothesis, many studies have observed that MSCs secrete cytokines, chemokines, and growth factors that could potentially repair injured cardiac tissue mainly through cardiac and vascular tissue growth and regeneration (Caplan and Dennis, 2006b; Liu and Hwang, 2005)....

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  • ...These proteins generally included cytokines, chemokines, and other growth factors (Caplan and Dennis, 2006a)....

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  • ...Recent reports have suggested that some of these reparative effects are mediated by paracrine factors secreted by MSCs (Caplan and Dennis, 2006a; Gnecchi et al., 2005, 2006; Schafer and Northoff, 2008)....

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  • ...The trophic effects of MSC transplantation on ameliorating the deleterious consequences of myocardial ischemia have been implicated in several studies (Caplan and Dennis, 2006a)....

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Journal ArticleDOI
TL;DR: The experimental origin of the concept of the population(s) referred to as mesenchymal stem cells and the experimental framework required to assess their stemness and function are revisited.

1,473 citations


Cites background from "Mesenchymal stem cells as trophic m..."

  • ...That is, if one function is to nurture HSCs and their progeny, then it is possible that nonhematopoietic cells may also benefit from a ‘‘nursing’’ effect conveyed by direct interaction with BMSCs and/or by paracrine stimuli (Caplan and Dennis, 2006)....

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Journal ArticleDOI
TL;DR: Evidence that leads to the proposal that during local injury, MSCs are released from their perivascular location, become activated, and establish a regenerative microenvironment by secreting bioactive molecules and regulating the local immune response is discussed.

1,402 citations


Cites background from "Mesenchymal stem cells as trophic m..."

  • ...Indeed, all of these disorders and conditions appear to be muted or cured by the injected or infused MSCs based on two generalizable therapeutic activities (Caplan and Dennis, 2006): immunomodulation and trophic activities (Figure 2)....

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References
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Journal ArticleDOI
04 Jul 2002-Nature
TL;DR: It is reported here that cells co-purifying with mesenchymal stem cells—termed here multipotent adult progenitor cells or MAPCs—differentiate, at the single cell level, not only into meschymal cells, but also cells with visceral mesoderm, neuroectoderm and endoderm characteristics in vitro.
Abstract: We report here that cells co-purifying with mesenchymal stem cells--termed here multipotent adult progenitor cells or MAPCs--differentiate, at the single cell level, not only into mesenchymal cells, but also cells with visceral mesoderm, neuroectoderm and endoderm characteristics in vitro. When injected into an early blastocyst, single MAPCs contribute to most, if not all, somatic cell types. On transplantation into a non-irradiated host, MAPCs engraft and differentiate to the haematopoietic lineage, in addition to the epithelium of liver, lung and gut. Engraftment in the haematopoietic system as well as the gastrointestinal tract is increased when MAPCs are transplanted in a minimally irradiated host. As MAPCs proliferate extensively without obvious senescence or loss of differentiation potential, they may be an ideal cell source for therapy of inherited or degenerative diseases.

5,475 citations

Journal ArticleDOI
05 Apr 2001-Nature
TL;DR: It is indicated that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease.
Abstract: Myocardial infarction leads to loss of tissue and impairment of cardiac performance The remaining myocytes are unable to reconstitute the necrotic tissue, and the post-infarcted heart deteriorates with time1 Injury to a target organ is sensed by distant stem cells, which migrate to the site of damage and undergo alternate stem cell differentiation2,3,4,5; these events promote structural and functional repair6,7,8 This high degree of stem cell plasticity prompted us to test whether dead myocardium could be restored by transplanting bone marrow cells in infarcted mice We sorted lineage-negative (Lin-) bone marrow cells from transgenic mice expressing enhanced green fluorescent protein9 by fluorescence-activated cell sorting on the basis of c-kit expression10 Shortly after coronary ligation, Lin- c-kitPOS cells were injected in the contracting wall bordering the infarct Here we report that newly formed myocardium occupied 68% of the infarcted portion of the ventricle 9 days after transplanting the bone marrow cells The developing tissue comprised proliferating myocytes and vascular structures Our studies indicate that locally delivered bone marrow cells can generate de novo myocardium, ameliorating the outcome of coronary artery disease

5,331 citations


"Mesenchymal stem cells as trophic m..." refers background in this paper

  • ...Whether HSCs differentiate into cardiac cells is a subject of debate [Orlic et al., 2001; Balsam et al., 2004; Kawada et al., 2004; Murry et al., 2004]; for an extensive review on this debate and on cardiac repair in general, see Laflamme and Murry [2005]....

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Journal ArticleDOI
TL;DR: The study of mesenchymal stem cells, whether isolated from embryos or adults, provides the basis for the emergence of a new therapeutic technology of self‐cell repair.

4,861 citations


"Mesenchymal stem cells as trophic m..." refers background in this paper

  • ...One class of multipotent adult progenitors is referred to as mesenchymal stem cells (MSCs) [Caplan, 1991]....

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Journal ArticleDOI
19 Sep 2003-Cell
TL;DR: The existence of Lin(-) c-kit(POS) cells with the properties of cardiac stem cells, which are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells are reported.

3,651 citations


"Mesenchymal stem cells as trophic m..." refers background in this paper

  • ...Additional complexities arise in light of recent evidence that cardiac tissue may itself contain stem cells [Beltrami et al., 2003] which could be the targets of ischemia-induced signaling, such as SDF-1, or are the targets of MSCFig....

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  • ...Additional complexities arise in light of recent evidence that cardiac tissue may itself contain stem cells [Beltrami et al., 2003] which could be the targets of ischemia-induced signaling, such as SDF-1, or are the targets of MSC- derived signals....

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Journal ArticleDOI
TL;DR: The bone marrow contains multipotent MSC, which can be easily isolated and cultured in vitro, and the possibility of their clinical use in cell and gene therapy is analyzed.
Abstract: Institute of Biological Medicine, Moscow The formation of the concept of a mesenchymal stem cell (MSC) is a priority of Russian biological science. A. Ya. Fridenshtein and his colleagues were the first who experimentally proved the existence of MSC. Osteogenic potential of fibroblastlike bone marrow cells of different mammalian species was demonstrated [25,26]. Fibroblast-like bone marrow cells often formed discrete adhesive colonies in vitro [27,28,47]. After heteroand orthotopic transplantation in vivo cloned cells from these colonies formed bone, cartilaginous, fibrous, and adipose tissues [48]. Intensive self-renewal and multipotency of fibroblast-like colony-forming cells from the bone marrow allowed Fridenshtein and Owen to formulate a concept of multipotent mesenchymal precursor cells (MPC) [62]. An ordered chain of finely regulated cell proliferation, migration, differentiation, and maturation processes underlies the formation of the majority of cell lineages in adult organisms. The earliest cell elements in this chain are stem cells (SC). Along with extensive self-renewal capacity, SC possess a great differentiation potential. Apart from well studied hemopoietic and intestinal SC, other SC classes were recently discovered in adult organism. Until recently it was considered that SC in adults can give rise to cell lines specific to tissues where these cells are located; however, new facts necessitated revision of this concept. Hemopoietic SC capable of differentiating into all cell elements of the blood, can also be a source of hepatic oval cells [65]; neural SC, precursors of neurons and glia [2,3], serve as the source of early and committed hemopoietic precursors [10]. MSC, a source of bone, cartilaginous, and adipose tissue cells, can differentiate into neural cells [46]. Tissue growth and reparation are associated with migration of uncommitted precursor cells from other tissues. During muscle tissue reparation mesenchymal SC migrate from the bone marrow into skeletal muscles [24]. Hence, in addition to capacity to unlimited division and reproduction of a wide spectrum of descendants of a certain differentiation line, adult SC are characterized by high plasticity. The existence of a rare type of somatic pluripotent SC, common precursors of all SC in an adult organism, is hypothesized [79]. Another important characteristic of SC is their migration from the tissue niche into circulation, which was experimentally proven for hemopoietic and MSC [69,73]. For activation of the differentiation program, circulating SC should get into an appropriate microenvironment [75,78]. A potent stimulus for investigation of SC is the possibility of their clinical use in cell and gene therapy. The bone marrow contains multipotent MSC, which can be easily isolated and cultured in vitro. It is therefore interesting to analyze some fundamental aspects of MSC biology and the possibilities of their clinical use. MSC descendants are involved in the formation of bones, cartilages, tendons, adipose and muscle tissues, and stroma maintaining the hemopoiesis [12,19,51]. The term MPC is used to denote MSC and their committed descendants capable of differentiating into at least two types of mature cells, which are present in the bone marrow and some mesenchymal tissues [16,19,57,82].

3,582 citations


"Mesenchymal stem cells as trophic m..." refers background or result in this paper

  • ...Recent studies [Mangi et al., 2003] document the effects of transplantedMSCs expressing the pro-survival gene Akt1, and the authors recognized that the molecules released by transplanted MSCs are important....

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  • ...Several groups studying the systemic or local administration of MSCs in cardiac repairmodels show co-localization of cardiac markers with implanted MSCs [Min et al., 2002; Shake et al., 2002;Mangi et al., 2003; Kawada et al., 2004; Nagaya et al., 2004]....

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