Chondrogenic Priming of Human Bone Marrow Stromal Cells: A Better Route to Bone Repair?

Farrell, Eric; Jagt, Olav P. van der; Koevoet, Wendy; Kops, Nicole; Manen, Christiaan J. van; Hellingman, Catharine A.; Jahr, Holger; O’Brien, Fergal J.; Verhaar, Jan A N; Weinans, Harrie; Osch, Gerjo J.V.M. van

doi:10.1089/ten.tea.2008.0297

Cited by 34 publications

(79 citation statements)

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“…This undesirable outcome results in terminal differentiation of chondrocytes, followed by ossification when transplanted in vivo subcutaneously [24,25] where they are exposed to high levels of vascularization, unlike articular cartilage. Recent studies argue that the observed terminal differentiation of in vitro differentiated MSCs is a direct result of the in vitro culture conditions, not of the natural differentiation process [50,51] inherent in these progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Cals et al have demonstrated that individual TGF-b subtypes orchestrate in vitro terminal differentiation [52]. Exploitation of these observations has lead to the in vitro chondrogenic priming of MSCs, followed by subsequent implantation and natural ossification, as an improved method to engineer bone for regenerative applications [24,53].…”

Section: Discussionmentioning

confidence: 99%

“…When transplanted subcutaneously, chondrogenically primed MSCs develop along a pathway toward endochondral ossification (EO), exhibiting features such as development of a bony collar, vascularization, osteoclastic resorbtion of the cartilage, and the presence of the hematopoietic foci [17,18]. In fact, MSCs in pellet cultures express collagen type I, indicating the development of osseous tissue, and markers of chondrocyte hypertrophy such as collagen type X, osteopontin (OPN), and MMP-13 expression, followed by alkaline phosphatase (ALP) activity and mineralization [17,[19][20][21][22][23][24][25]. Interestingly, when MSCs are directly placed in an articular cartilage defect, their spontaneous differentiation results in expression of collagen type II without collagen type X, indicating the development of an articular-like phenotype [26].…”

Section: Introductionmentioning

confidence: 99%

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Growth Differentiation Factor-5 Enhances In Vitro Mesenchymal Stromal Cell Chondrogenesis and Hypertrophy

Coleman

Vaughan

Browe

et al. 2013

Stem Cells and Development

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The regenerative potential for adult bone marrow-derived mesenchymal stromal cells (MSCs) has been extensively investigated in the setting of arthritic disease and focal cartilage defects. In vitro chondrogenic differentiation of MSCs is regularly accomplished by the widely used pellet culture system where MSCs are maintained in high-density pellets to mimic mesenchymal condensation during development. Supplementation of chondrogenic MSC pellet cultures with growth differentiation factor-5 (GDF-5), a highly regulated gene in the chondrogenic phase of endochondral ossification (EO), was investigated here under the hypothesis that GDF-5 will enhance the chondrogenic differentiation of MSCs, thereby supporting their entry into ossification. The supplementation of chondrogenic MSC pellets with the recombinant human GDF-5 protein significantly enhanced MSC chondrogenic differentiation, as demonstrated by enhanced collagen type II and sulfated glycosaminoglycan (GAG) incorporation into the extracellular matrix. Increased P-SMADs 1-5-8 were observed in pellets treated with GDF-5 and transforming growth factor (TGF)-b 3 when compared to the pellets treated with TGF-b 3 alone, demonstrated by immunostaining and western blot analysis of the chondrogenic pellet extract. A concurrent increase in alkaline phosphatase, collagen types I and X, and osteopontin secretion indicated a transition of these cultures to hypertrophy. Together, these data support the application of GDF-5 to enhance MSC chondrogenic differentiation and hypertrophy as a precursor to EO.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Growth Differentiation Factor-5 Enhances In Vitro Mesenchymal Stromal Cell Chondrogenesis and Hypertrophy

Coleman

Vaughan

Browe

et al. 2013

Stem Cells and Development

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show abstract

“…However, the chondrogenic priming of human MSC in the absence of a scaffold [40], in distinct hydrogels [51], on a collagen-GAG scaffold [38] or on HA/TCP particles [50] had no [38,40,51] or little [50] success regarding heterotopic new bone formation in mice. Nevertheless, we were encouraged to use b-TCP particles in combination with chondrogenic priming to achieve or even enhance bone formation since b-TCP particles supported in vitro chondrogenesis of MSC of donor G. We have here provided evidence that, if human MSC pellets contain fibrin and b-TCP particles smaller than 1.4 mm, chondrogenic pre-induction can strongly support the endochondral formation of heterotopic bone, including haematopoietic tissue, while the same unprimed b-TCP/MSC composites underwent intramembranous bone formation without marrow attraction.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, no HA/TCP ceramic was included in these studies, so whether b-TCP and CDHA are inferior to the gold standard HA/TCP in ectopic bone formation capability could not be determined. In general, in vitro stimulation of MSC toward the osteogenic lineage before transplantation, intended as an approach to enhance or speed up intramembranous bone formation or overcome donor variability, yielded disappointing results independent of whether dexamethasone [14,37,38] or vitamin D [39] was used for osteogenic priming.…”

Section: Introductionmentioning

confidence: 99%

Chondrogenic pre-induction of human mesenchymal stem cells on β-TCP: Enhanced bone quality by endochondral heterotopic bone formation

et al. 2010

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Differentiation of Vascular Stem Cells Contributes to Ectopic Calcification of Atherosclerotic Plaque

et al. 2016

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The cellular and molecular basis of vascular calcification (VC) in atherosclerosis is not fully understood. Here, we investigate role of resident/circulating progenitor cells in VC and contribution of inflammatory plaque environment to this process. Vessel-derived stem/progenitor cells (VSCs) and mesenchymal stem cells (MSCs) isolated from atherosclerotic ApoE 2/2 mice showed significantly more in vitro osteogenesis and chondrogenesis than cells generated from control C57BL/6 mice. To assess their ability to form bone in vivo, cells were primed chondrogenically or cultured in control medium on collagen glycosaminoglycan scaffolds in vitro prior to subcutaneous implantation in ApoE 2/2 and C57BL/6 mice using a crossover study design. Atherosclerotic ApoE 2/2 MSCs and VSCs formed bone when implanted in C57BL/6 mice. In ApoE 2/2 mice, these cells generated more mature bone than C57BL/6 cells. The atherosclerotic in vivo environment alone promoted bone formation by implanted C57BL/6 cells. Un-primed C57BL/6 VSCs were unable to form bone in either mouse strain. Treatment of ApoE 2/2 VSC chondrogenic cultures with interleukin (IL)-6 resulted in significantly increased glycosaminoglycan deposition and expression of characteristic chondrogenic genes at 21 days. In conclusion, resident vascular cells from atherosclerotic environment respond to the inflammatory milieu and undergo calcification. IL-6 may have a role in aberrant differentiation of VSCs contributing to vascular calcification in atherosclerosis. STEM CELLS 2016;34:913-923 SIGNIFICANCE STATEMENTAlthough chronic heart disease affects over 15 million patients in the United States alone, the pathophysiology of atherosclerosis and vascular calcification is not fully understood. Cues from this study hold promise to unfold the possible mechanisms underlying vascular calcification observed in atherosclerotic plaque. Our data indicates that the atherosclerotic environment has a fundamental effect on resident blood vessel stem/progenitor cells priming them to respond to the local inflammatory milieu to differentiate and calcify. Additionally, we have identified IL-6 as a potential inflammatory mediator. The role of IL-6 presented in this study provides implications for therapeutic applications to prevent vascular calcification.

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Chondrogenic Priming of Human Bone Marrow Stromal Cells: A Better Route to Bone Repair?

Cited by 34 publications

References 42 publications

Growth Differentiation Factor-5 Enhances In Vitro Mesenchymal Stromal Cell Chondrogenesis and Hypertrophy

Growth Differentiation Factor-5 Enhances In Vitro Mesenchymal Stromal Cell Chondrogenesis and Hypertrophy

Chondrogenic pre-induction of human mesenchymal stem cells on β-TCP: Enhanced bone quality by endochondral heterotopic bone formation

Differentiation of Vascular Stem Cells Contributes to Ectopic Calcification of Atherosclerotic Plaque

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