Induction of Mesenchymal Progenitor Cells with Chondrogenic Property from Mouse-Induced Pluripotent Stem Cells

Teramura, Takeshi; Onodera, Yuta; Mihara, Toshihiro; Hosoi, Yoshihiko; Hamanishi, Chiaki; Fukuda, Kanji

doi:10.1089/cell.2009.0086

Cited by 62 publications

(49 citation statements)

References 43 publications

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“…We further demonstrate that the same technique has potential use for repairing defects in native articular cartilage, as evidenced by the formation of cartilage-cartilage interface with integration strengths of 400 kPa. Conceivably, the same technique could be extended to bioengineer other tissues (39), such as tendon or meniscus, and to the use of other cell sources, such as embryonic and induced pluripotent stem cells (40,41).…”

Section: Discussionmentioning

confidence: 99%

Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation

Bhumiratana

Eton

Oungoulian

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

171

189

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The efforts to grow mechanically functional cartilage from human mesenchymal stem cells have not been successful. We report that clinically sized pieces of human cartilage with physiologic stratification and biomechanics can be grown in vitro by recapitulating some aspects of the developmental process of mesenchymal condensation. By exposure to transforming growth factor-β, mesenchymal stem cells were induced to condense into cellular bodies, undergo chondrogenic differentiation, and form cartilagenous tissue, in a process designed to mimic mesenchymal condensation leading into chondrogenesis. We discovered that the condensed mesenchymal cell bodies (CMBs) formed in vitro set an outer boundary after 5 d of culture, as indicated by the expression of mesenchymal condensation genes and deposition of tenascin. Before setting of boundaries, the CMBs could be fused into homogenous cellular aggregates giving rise to well-differentiated and mechanically functional cartilage. We used the mesenchymal condensation and fusion of CMBs to grow centimeter-sized, anatomically shaped pieces of human articular cartilage over 5 wk of culture. For the first time to our knowledge biomechanical properties of cartilage derived from human mesenchymal cells were comparable to native cartilage, with the Young's modulus of >800 kPa and equilibrium friction coeffcient of <0.3. We also demonstrate that CMBs have capability to form mechanically strong cartilage-cartilage interface in an in vitro cartilage defect model. The CMBs, which acted as "lego-like" blocks of neocartilage, were capable of assembling into human cartilage with physiologic-like structure and mechanical properties.

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Section: Discussionmentioning

confidence: 99%

Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation

Bhumiratana

Eton

Oungoulian

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

171

189

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“…For example, Oldershaw and colleagues developed a protocol involving temporally-varied plating densities, matrix substrates, and growth factors to achieve a high percentage of chondrocyte-like cells from human embryonic stem cells (34). Similarly, several studies using mouse or human iPSCs have used 3D embryoid bodies as an intermediate step leading to subsequent chondrogenic differentiation (28)(29)(30). We determined that short-term exposure to BMP-4 in serum-free micromass cultures was effective at initiating chondrogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…proliferation of iPSC-derived MSC-like cells (30). However, it is important to note that GFP+ cells lost the ability to form homogeneous cartilaginous pellets after being passaged three times, suggesting that whereas limited passaging may prime or preferentially expand cells with the most chondrogenic potential, extensive expansion may lead to dedifferentiation that limits the chondrogenic capacity of the cells.…”

Section: Discussionmentioning

confidence: 99%

“…Chondrogenesis can be further enhanced by recapitulating features of mesenchymal condensation using 3D culture systems such as embryoid bodies (23), micromasses (24,25), pellets (26), or scaffolds (27). These techniques have also been effective in initial studies with mouse and human iPSCs (28)(29)(30)(31). However, the inability to differentiate every pluripotent cell toward the chondrogenic lineage has limited the potential to engineer a tissue with uniform cartilaginous matrix.…”

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confidence: 99%

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Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells

Diekman

Christoforou

Willard

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

234

250

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The development of regenerative therapies for cartilage injury has been greatly aided by recent advances in stem cell biology. Induced pluripotent stem cells (iPSCs) have the potential to provide an abundant cell source for tissue engineering, as well as generating patient-matched in vitro models to study genetic and environmental factors in cartilage repair and osteoarthritis. However, both cell therapy and modeling approaches require a purified and uniformly differentiated cell population to predictably recapitulate the physiological characteristics of cartilage. Here, iPSCs derived from adult mouse fibroblasts were chondrogenically differentiated and purified by type II collagen (Col2)-driven green fluorescent protein (GFP) expression. Col2 and aggrecan gene expression levels were significantly up-regulated in GFP+ cells compared with GFP− cells and decreased with monolayer expansion. An in vitro cartilage defect model was used to demonstrate integrative repair by GFP+ cells seeded in agarose, supporting their potential use in cartilage therapies. In chondrogenic pellet culture, cells synthesized cartilagespecific matrix as indicated by high levels of glycosaminoglycans and type II collagen and low levels of type I and type X collagen. The feasibility of cell expansion after initial differentiation was illustrated by homogenous matrix deposition in pellets from twicepassaged GFP+ cells. Finally, atomic force microscopy analysis showed increased microscale elastic moduli associated with collagen alignment at the periphery of pellets, mimicking zonal variation in native cartilage. This study demonstrates the potential use of iPSCs for cartilage defect repair and for creating tissue models of cartilage that can be matched to specific genetic backgrounds.chondrocyte | bone morphogenetic proteins | transforming growth factor-beta | cartilage micromechanics | cartilage regeneration

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“…Induced pluripotent stem cells (iPSCs) are pluripotent cells derived from terminally differentiated cells by dedifferentiation. The generation of iPSCs creates the possibility of generating tissue-specific cells, including HSCs [63][64][65][66][67][68] or MSCs [69][70][71][72][73][74][75][76], but further study is required before clinical application of iPSCs can commence. Taken together, immune reconstruction and modification of genetic predisposition of hematopoietic stem cells are important for radical cure of IBD.…”

Section: Intestinal Stem Cells and Other Stem Cells In Ibdmentioning

confidence: 99%

Stem cell therapy for inflammatory bowel disease

2015

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Inflammatory bowel disease (IBD) could be curable by ''immune rest'' and correction of the genetic predisposition inherent in allogeneic hematopoietic stem cell transplantation. However, balancing risks against benefits remains challenging. The application of mesenchymal stem cells (MSCs) serving as a site-regulated ''drugstore'' is a recent concept, which suggests the possibility of an alternative treatment for many intractable diseases such as IBD. Depending on the required function of MSC, such as a cell provider, immune moderator, and/or trophic resource, MSC therapy should be optimized to maximize its therapeutic benefit. Therapeutic effects do not always require full engraftment of MSCs. Therefore, optimization of pleiotropic gut trophic factors produced by MSCs, which favoring not only regulating immune responses but also promoting tissue repair, must directly enhance new drug discoveries for treatment of IBD. Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and patients. However, the translational arm of stem cell science remains in a relatively primitive state.Although several clinical studies using MSCs have been initiated, early results suggest several inherent problems. In each study, optimization of MSC therapy appears to be the most urgent problem, and can be resolved only by scientifically unveiling the mechanisms of therapeutic action. In the present review, the authors outline how such information would facilitate the critical steps in the paradigm shift from basic research on stem cell biology to clinical practice of regenerative medicine for conquering IBD in the near future.

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Induction of Mesenchymal Progenitor Cells with Chondrogenic Property from Mouse-Induced Pluripotent Stem Cells

Cited by 62 publications

References 43 publications

Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation

Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation

Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells

Stem cell therapy for inflammatory bowel disease

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