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Journal ArticleDOI

Bone marrow as a potential source of hepatic oval cells.

14 May 1999-Science (American Association for the Advancement of Science)-Vol. 284, Iss: 5417, pp 1168-1170
TL;DR: A stem cell associated with the bone marrow has epithelial cell lineage capability and a proportion of the regenerated hepatic cells were shown to be donor-derived.
Abstract: Bone marrow stem cells develop into hematopoietic and mesenchymal lineages but have not been known to participate in production of hepatocytes, biliary cells, or oval cells during liver regeneration. Cross-sex or cross-strain bone marrow and whole liver transplantation were used to trace the origin of the repopulating liver cells. Transplanted rats were treated with 2-acetylaminofluorene, to block hepatocyte proliferation, and then hepatic injury, to induce oval cell proliferation. Markers for Y chromosome, dipeptidyl peptidase IV enzyme, and L21-6 antigen were used to identify liver cells of bone marrow origin. From these cells, a proportion of the regenerated hepatic cells were shown to be donor-derived. Thus, a stem cell associated with the bone marrow has epithelial cell lineage capability.
Citations
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Journal ArticleDOI
01 Nov 2001-Nature
TL;DR: Stem cell biology has come of age: Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine.
Abstract: Stem cell biology has come of age. Unequivocal proof that stem cells exist in the haematopoietic system has given way to the prospective isolation of several tissue-specific stem and progenitor cells, the initial delineation of their properties and expressed genetic programmes, and the beginnings of their utility in regenerative medicine. Perhaps the most important and useful property of stem cells is that of self-renewal. Through this property, striking parallels can be found between stem cells and cancer cells: tumours may often originate from the transformation of normal stem cells, similar signalling pathways may regulate self-renewal in stem cells and cancer cells, and cancer cells may include 'cancer stem cells' - rare cells with indefinite potential for self-renewal that drive tumorigenesis.

8,999 citations

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
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

Journal ArticleDOI
TL;DR: The targets and mechanisms of M SC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches are discussed.
Abstract: Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of several effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discusses the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.

3,142 citations

Journal ArticleDOI
04 May 2001-Cell
TL;DR: It is shown that rare cells that home to bone marrow can LTR primary and secondary recipients, and this finding may contribute to clinical treatment of genetic disease or tissue repair.

2,773 citations


Cites background from "Bone marrow as a potential source o..."

  • ...Bone marrow transplantation itself might prove useful in the treatment of some forms(Petersen et al., 1999; Lagasse et al., 2000)....

    [...]

  • ...…showed that a bone marrow population (Theise et al., 2000a), we hypothesize that the same cells enriched for HSC can differentiate into mature hepatothat reconstitute hematopoiesis can also differentiate cytes in the liver of rodents (Petersen et al., 1999; Theise into nonhematopoietic tissues....

    [...]

References
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Journal ArticleDOI
06 Mar 1998-Science
TL;DR: Transplantation of genetically marked bone marrow into immunodeficient mice revealed that marrow-derived cells migrate into areas of induced muscle degeneration, undergo myogenic differentiation, and participate in the regeneration of the damaged fibers.
Abstract: Growth and repair of skeletal muscle are normally mediated by the satellite cells that surround muscle fibers. In regenerating muscle, however, the number of myogenic precursors exceeds that of resident satellite cells, implying migration or recruitment of undifferentiated progenitors from other sources. Transplantation of genetically marked bone marrow into immunodeficient mice revealed that marrow-derived cells migrate into areas of induced muscle degeneration, undergo myogenic differentiation, and participate in the regeneration of the damaged fibers. Genetically modified, marrow-derived myogenic progenitors could potentially be used to target therapeutic genes to muscle tissue, providing an alternative strategy for treatment of muscular dystrophies.

2,881 citations

Journal Article
TL;DR: The data indicate that oval cells can differentiate to hepatocytes and may have an important physiological function as a source of major serum proteins when hepatocytes are unable to synthesize these proteins.
Abstract: The Solt-Farber protocol, in the absence of an initiating agent, was used to examine the precursor-product relationship between oval cells and hepatocytes in rat liver. The animals were administered 2-acetylaminofluorene (AAF) by gavage for 2 wk combined with partial hepatectomy 1 wk after administering AAF Two dose levels of AAF were used: 9- and 21-mg total dose for animals in Groups I and II, respectively. [3H]Thymidine was administered i.p. to one-half of the animals at Day 6 post-partial hepatectomy. Animals were sacrificed 7, 9, 11, and 13 days after surgery. Only oval cells became labeled on Day 7 in both groups. On Day 9 both labeled oval cells and labeled basophilic hepatocytes were present in Group I, whereas in Group II only oval cells remained labeled. On Days 11 and 13 both oval cells and basophilic hepatocytes were labeled in both groups. The total amount of radioactivity in Group II livers remained the same on Day 9 when only labeled oval cells were present and on Days 11 and 13 when both labeled oval cells and labeled basophilic hepatocytes were present. The calculated half-life for basophilic hepatocytes was about 50 h. The differentiation of oval cells into basophilic hepatocytes was delayed in Group II as compared to Group I, and the higher dose of AAF also induced the formation of both intestinal metaplasia and bile duct formation. In situ hybridization with an alpha-fetoprotein probe showed a strong expression in groups of typical oval cells and in cells arranged in duct-like structures. In addition a transient expression of AFP was also observed in the areas of basophilic hepatocytes 9 to 11 days after partial hepatectomy. Administration of AAF decreased the level of albumin mRNA in preexisting hepatocytes and caused a significant decrease of serum albumin. In contrast, oval cells showed a strong albumin expression, and basophilic hepatocytes formed islands of albumin-expressing cells. Oval cells and the foci of early basophilic hepatocytes lacked glucose-6-phosphatase activity. At Day 13 significant numbers of basophilic hepatocytes were positive for glucose-6-phosphatase. Oval cells were strongly gamma-glutamyltranspeptidase positive, whereas the foci of basophilic hepatocytes were negative for gamma-glutamyltranspeptidase. Only occasionally were transiently gamma-glutamyltranspeptidase-positive hepatocytes observed in basophilic foci. In summary our data indicate that oval cells can differentiate to hepatocytes and may have an important physiological function as a source of major serum proteins when hepatocytes are unable to synthesize these proteins.

316 citations

Journal ArticleDOI
TL;DR: The data obtained from the mouse study strongly suggest that hematopoietic stem cells residing in the donor liver are responsible for mixed chimerism and maintenance of tolerance after liver transplantation.
Abstract: Recently, cases have been reported in which a mixed chimeric state of blood cells is established after liver transplantation. Because the established chimerism may have aided in the induction of donor-specific tolerance, the mechanism responsible for this chimerism is of clinical importance. To establish this, we examined cells in adult mouse liver and identified the presence of c-kit+ Sca-1+ Lin(lo/-) cells. These cells were capable of forming in vivo as well as in vitro colonies. Furthermore, the cells could reconstitute bone marrow of lethally irradiated recipient mice for at least 12 months. These data obtained from the mouse study strongly suggest that hematopoietic stem cells residing in the donor liver are responsible for mixed chimerism and maintenance of tolerance after liver transplantation.

309 citations

Journal Article
TL;DR: The SCF/c-kit system may, possibly in combination with other growth factor/receptor systems, be involved in the early activation of the hepatic stem cells as well as in the expansion and differentiation of oval cells.

284 citations

Journal ArticleDOI
TL;DR: Both the GVHD propensity and tolerogenicity in these experiments were closely associated with recipient tissue chimerism 30 and 100 days after the experiments began, and these observations provide guidelines that should be considered in devising leukocyte augmentation protocols for human whole organ recipients.
Abstract: The persistence of microchimerism in human whole organ recipients years or decades after transplantation (1, 2) reflects the migration long before of bone marrow-derived donor leukocytes from the allografts (3, 4). We have postulated that these immunocompetent donor cells represent one limb of initially antagonistic but ultimately attenuated or abrogated host-versus-graft (HVG,* rejection) and graft-versus-host (GVH) reactions (1-5) (Fig. 1). We describe here a study in rats of the HVG and GVH components of this two-way immunologic paradigm. The clinical and histopathologic expression of the two arms with and without immunosuppression was correlated with the quantity and quality of recipient tissue chimerism and with the development of donor-specific tolerance following transplantation from Lewis (LEW) donors to Brown Norway (BN) recipients of different organs (intestine, liver, heart, kidney) and of different free leukocyte suspensions (bone marrow, lymph nodes, spleen, thymus, and blood). Figure 1 Dualistic immune reactions of host-versus-graft (HVG) and graft-versus-host (GVH) in the two-way paradigm of transplantation immunology. Following the acute reaction, the evolution of tolerance of each leukocyte population to the other is seen as a low-grade ... Although the results leave numerous questions unanswered about basic mechanisms, they cast light on 4 issues that are relevant to planning of clinical tolerance induction protocols: (1) The relative risk of producing clinical GVHD with the tranplantation of different organs and with infusion of a standardized dose of leukocytes obtained from various lymphoid organs, (2) the relative tolerogenicity of the parenchymal organs and the leukocyte suspensions, (3) correlation of 1 and 2 with the density and lineage profile of the chimerism in recipient tissues and, (4) the relation to the quantity and lineage composition of chimerism to chronic rejection.

221 citations