<i>In vitro</i>cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis

Sekiya, Ichiro; Vuoristo, Jussi; Larson, Benjamin L.; Prockop, Darwin J.

doi:10.1073/pnas.052716199

Cited by 602 publications

(547 citation statements)

References 40 publications

(33 reference statements)

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“…In stark contrast to findings in previously reported studies in which BMP-6 was used to induce chondrogenesis (24,28,30), the results of this study demonstrate that BMP-6 not only is a strong inducer of 2 primary chondrogenic markers, AGC1 and COL2A1, but also is a strong inhibitor of the hypertrophic/ endochondral ossification pathway, as indicated by significant decreases in COL10A1 gene expression and immunolabeling compared with other chondrogenic conditions (Figures 4 and 5). It is possible that a longer time course of study would reveal an increase in COL10A1 gene expression with BMP-6, as has been observed with other cell types (39,45).…”

Section: Discussioncontrasting

confidence: 99%

“…It is possible that a longer time course of study would reveal an increase in COL10A1 gene expression with BMP-6, as has been observed with other cell types (39,45). However, it should be noted that, in studies by Sekiya et al (28,30), PCR analysis revealed an increase in COL10A1 gene expression relative to day-0 controls occurring as early as 7 days from treatment initiation, which is directly opposite the results obtained in the present study.…”

Section: Discussioncontrasting

confidence: 75%

“…The concentrations of TGF␤1, TGF␤3, and IGF-1 used for chondrogenic differentiation were based on previous studies of MSCs and ADAS cells (13)(14)(15)17,18,21,(24)(25)(26)(27)(28)30,31). To determine the dose-response effect of BMP-6, the effects of BMP-6 at a range of concentrations (5-500 ng/ml) on the expression of COL1A1, COL2A1, COL10A1, and AGC1 gene transcripts were examined, showing maximum stimulation of COL2A1 and AGC1 and suppression of COL10A1 at 500 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

“…These cells also can be induced toward a chondrogenic phenotype with growth factors including insulin-like growth factor 1 (IGF-1), TGF␤2, and bone morphogenetic protein 6 (BMP-6), in addition to TGF␤1 and TGF␤3 (23)(24)(25)(26)(27)(28)(29)(30)(31). Results of previous studies suggest that TGF␤2 and TGF␤3 are more effective than TGF␤1 in promoting glycosaminoglycan and type II collagen accumulation in micromass pellet culture (25).…”

mentioning

confidence: 99%

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Potent induction of chondrocytic differentiation of human adipose‐derived adult stem cells by bone morphogenetic protein 6

Estes

Guilak

2006

Arthritis & Rheumatism

269

212

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Objective. Recent studies have identified an abundant source of multipotent progenitor cells in subcutaneous human adipose tissue, termed human adiposederived adult stem cells (ADAS cells). In response to specific media formulations, including transforming growth factor ␤1 (TGF␤1), these cells exhibit significant ability to differentiate into a chondrocyte-like phenotype, expressing cartilage-specific genes and proteins such as aggrecan and type II collagen. However, the influence of other growth factors on the chondrogenic differentiation of ADAS cells is not fully understood. This study was undertaken to investigate the effects of TGF␤1, TGF␤3, insulin-like growth factor 1, bone morphogenetic protein 6 (BMP-6), and dexamethasone, in various combinations, on the chondrogenic potential of ADAS cells in alginate beads.Methods. The chondrogenic response of alginateencapsulated ADAS cells was measured by quantitative polymerase chain reaction, 3 H-proline and 35 S-sulfate incorporation, and immunolabeling for specific extracellular matrix components.Results. Significant differences in chondrogenesis were observed under the different culture conditions for all outcomes measured. Most notably, BMP-6 upregulated AGC1 and COL2A1 expression by an average of 205-fold and 38-fold, respectively, over day-0 controls, while down-regulating COL10A1 expression by ϳ2-fold.Conclusion. These findings suggest that BMP-6 is a potent inducer of chondrogenesis in ADAS cells, in contrast to mesenchymal stem cells, which exhibit increased expression of type X collagen and a hypertrophic phenotype in response to BMP-6. Combinations of growth factors containing BMP-6 may provide a novel means of regulating the differentiation of ADAS cells for applications in the tissue-engineered repair or regeneration of articular cartilage.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussioncontrasting

confidence: 75%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Potent induction of chondrocytic differentiation of human adipose‐derived adult stem cells by bone morphogenetic protein 6

Estes

Guilak

2006

Arthritis & Rheumatism

269

212

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“…The transcriptional response to stimulation with BMP has been analyzed in different cellular systems [5,[29][30][31] , but not previously in cells of lymphoid origin. Up-regulation of ID genes is an important event in this response, and has been demonstrated to be dependent on Smad phosphorylation [8].…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-b superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4 + T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4 + T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

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Stem Cells

Sylvester

Longaker²

2004

Arch Surg

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egenerative medicine and emerging biotechnologies stand to revolutionize the practice of medicine. Advancements in stem cell biology, including embryonic and postnatal somatic stem cells, have made the prospect of tissue regeneration a potential clinical reality. Short of reproductive cloning, these same technologies, properly used, could allow for the creation of replacement tissue for the deficient host. To provide a concise review for surgeons on the current science and biology of stem cells, we surveyed the scientific literature, MEDLINE, and relevant political headlines that illuminate the stem cell discussion; the issues are summarized in this review. Building on this conceptual framework, the related issues of clinical promise and the political debate enveloping this emerging technology are examined. A basic understanding of stem cell biology is paramount to stay informed of this emerging technology and the national debate.

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In vitrocartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis

Cited by 602 publications

References 40 publications

Potent induction of chondrocytic differentiation of human adipose‐derived adult stem cells by bone morphogenetic protein 6

Potent induction of chondrocytic differentiation of human adipose‐derived adult stem cells by bone morphogenetic protein 6

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Stem Cells

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