Macromer density influences mesenchymal stem cell chondrogenesis and maturation in photocrosslinked hyaluronic acid hydrogels

Erickson, Isaac E.; Huang, Alice H.; Sengupta, Swarnali; Kestle, Sydney R.; Burdick, Jason A.; Mauck, Robert L.

doi:10.1016/j.joca.2009.07.003

Cited by 169 publications

(192 citation statements)

References 43 publications

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“…In agreement with previous studies (Bian et al, 2013;Erickson et al, 2009), a denser, presumably stiffer, PCM also develops in the higher concentration hydrogels to which the MSCs can adhere and sense. In addition to a stiffer micro-environment for MSCs in the 4 % hydrogels, it is also reasonable to assume that the more developed PCM in these constructs leads to an increase in the number of integrin binding sites per cell.…”

Section: Discussionsupporting

confidence: 92%

“…Irrespective of hydrogel stiffness, this permissive medium did not support chondrogenesis of MSCs. As seen previously, when maintained in a medium supplemented with TGF-β3, cartilage matrix production was inhibited in stiffer hydrogels (Bian et al, 2013;Erickson et al, 2009). One potential explanation for this is that diffusivity of biomolecules (such as TGF-β3) would be lower in the stiffer, denser 4 % hydrogels; however, these hydrogels are still 96 % fluid and are therefore not expected to significantly inhibit biomolecule diffusivity.…”

Section: Discussionsupporting

confidence: 51%

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The pericellular environment regulates cytoskeletal development and the differentiation of mesenchymal stem cells and determines their response to hydrostatic pressure

Steward

Wagner²,

Kelly³

2013

eCM

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The objective of this study was to examine the interplay between matrix stiffness and hydrostatic pressure (HP) in regulating chondrogenesis of mesenchymal stem cells (MSCs) and to further elucidate the mechanotransductive roles of integrins and the cytoskeleton. MSCs were seeded into 1 %, 2 % or 4 % agarose hydrogels and exposed to cyclic hydrostatic pressure. In a permissive media, the stiffer hydrogels supported an osteogenic phenotype, with little evidence of chondrogenesis observed regardless of the matrix stiffness. In a chondrogenic media, the stiffer gels suppressed cartilage matrix production and gene expression, with the addition of RGDS (an integrin blocker) found to return matrix synthesis to similar levels as in the softer gels. Vinculin, actin and vimentin organisation all adapted within stiffer hydrogels, with the addition of RGDS again preventing these changes. While the stiffer gels inhibited chondrogenesis, they enhanced mechanotransduction of HP. RGDS suppressed the mechanotransduction of HP, suggesting a role for integrin binding as a regulator of both matrix stiffness and HP. Intermediate filaments also appear to play a role in the mechanotransduction of HP, as only vimentin organisation adapted in response to this mechanical stimulus. To conclude, the results of this study demonstrate that matrix density and/or stiffness modulates the development of the pericellular matrix and consequently integrin binding and cytoskeletal structure. The study further suggests that physiological cues such as HP enhance chondrogenesis of MSCs as the pericellular environment matures and the cytoskeleton adapts, and points to a novel role for vimentin in the transduction of HP.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 51%

The pericellular environment regulates cytoskeletal development and the differentiation of mesenchymal stem cells and determines their response to hydrostatic pressure

Steward

Wagner²,

Kelly³

2013

eCM

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“…Recent in vitro studies have demonstrated successful chondrogenesis of hMSCs photoencapsulated in HA hydrogels formed through cross-linking of HA modified with methacrylate groups (27)(28)(29). However, it still remains a challenge to recapitulate the functional properties of the native articular cartilage using only hMSCs, particularly compared with donor-matched articular chondrocytes, as shown in a bovine model (30,31).…”

Section: Discussionmentioning

confidence: 99%

Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis

Bian

Guvendiren

Mauck

et al. 2013

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

347

298

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Methacrylated hyaluronic acid (HA) hydrogels provide a backbone polymer with which mesenchymal stem cells (MSCs) can interact through several cell surface receptors that are expressed by MSCs, including CD44 and CD168. Previous studies showed that this 3D hydrogel environment supports the chondrogenesis of MSCs, and here we demonstrate through functional blockade that these specific cell-material interactions play a role in this process. Beyond matrix interactions, cadherin molecules, a family of transmembrane glycoproteins, play a critical role in tissue development during embryogenesis, and N-cadherin is a key factor in mediating cellcell interactions during mesenchymal condensation and chondrogenesis. In this study, we functionalized HA hydrogels with Ncadherin mimetic peptides and evaluated their role in regulating chondrogenesis and cartilage matrix deposition by encapsulated MSCs. Our results show that conjugation of cadherin peptides onto HA hydrogels promotes both early chondrogenesis of MSCs and cartilage-specific matrix production with culture, compared with unmodified controls or those with inclusion of a scrambled peptide domain. This enhanced chondrogenesis was abolished via treatment with N-cadherin-specific antibodies, confirming the contribution of these N-cadherin peptides to chondrogenesis. Subcutaneous implantation of MSC-seeded constructs also showed superior neocartilage formation in implants functionalized with N-cadherin mimetic peptides compared with controls. This study demonstrates the inherent biologic activity of HA-based hydrogels, as well as the promise of biofunctionalizing HA hydrogels to emulate the complexity of the natural cell microenvironment during embryogenesis, particularly in stem cell-based cartilage regeneration.M esenchymal stem cells (MSCs) have emerged as a clinically relevant cell source for regenerative medicine due to their potential to differentiate into several mesenchymal lineages including cartilage, bone, and fat (1, 2). The multipotent differentiation of MSCs is tightly regulated by both soluble and physical cues present in the pericellular microenvironment, including cell-cell and cell-matrix interactions, cues that can be engineered into a variety of natural and synthetic biomaterial scaffolds (3). These materials may be either permissive to chondrogenesis (inert materials including agarose and PEG) or inductive to chondrogenesis by mimicking components of the natural pericellular microenvironment (4, 5). For example, photopolymerizable hydrogels composed of methacrylated (Me) hyaluronic acid (HA) may provide biological cues such as CD44 and CD168 interactions based on the role of HA in cellular signaling (6-8) (Fig. 1). Coincident with the onset of condensation and the first appearance of cartilage in the embryo is the appearance of specific binding sites for HA on bud limb mesenchymal cells (9). Large HA molecules are involved in the aggregation of these cells during condensation via multivalent cross-bridging (10), and HA has already been shown to enhan...

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“…These gels support both human and bovine MSC chondrogenesis [12,17]. In this study, we used a 1% w/vol HA formulation that maximizes matrix formation by juvenile bovine MSCs [18]. Similar to pellets, bovine MSCs in this three-dimensional context were highly age-dependent with fetal and juvenile MSCs producing robust samples with compressive properties reaching approximately 20% of native tissue values within 3 weeks.…”

Section: Discussionmentioning

confidence: 99%

Cartilage Matrix Formation by Bovine Mesenchymal Stem Cells in Three-dimensional Culture Is Age-dependent

Erickson

Veen

Sengupta

et al. 2011

Clinical Orthopaedics &Amp; Related Research

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Background Cartilage degeneration is common in the aged, and aged chondrocytes are inferior to juvenile chondrocytes in producing cartilage-specific extracellular matrix. Mesenchymal stem cells (MSCs) are an alternative cell type that can differentiate toward the chondrocyte phenotype. Aging may influence MSC chondrogenesis but remains less well studied, particularly in the bovine system. Questions/purposes The objectives of this study were (1) to confirm age-related changes in bovine articular cartilage, establish how age affects chondrogenesis in cultured pellets for (2) chondrocytes and (3) MSCs, and (4) determine age-related changes in the biochemical and biomechanical development of clinically relevant MSC-seeded hydrogels. Methods Native bovine articular cartilage from fetal (n = 3 donors), juvenile (n = 3 donors), and adult (n = 3 donors) animals was analyzed for mechanical and biochemical properties (n = 3-5 per donor). Chondrocyte and MSC pellets (n = 3 donors per age) were cultured for 6 weeks before analysis of biochemical content (n = 3 per donor). Bone marrow-derived MSCs of each age were also cultured within hyaluronic acid hydrogels for 3 weeks and analyzed for matrix deposition and mechanical properties (n = 4 per age). Results Articular cartilage mechanical properties and collagen content increased with age. We observed robust matrix accumulation in three-dimensional pellet culture by fetal chondrocytes with diminished collagen-forming capacity in adult chondrocytes. Chondrogenic induction of MSCs was greater in fetal and juvenile cell pellets. Likewise, fetal and juvenile MSCs in hydrogels imparted greater matrix and mechanical properties. Conclusions Donor age and biochemical microenvironment were major determinants of both bovine chondrocyte and MSC functional capacity. Clinical Relevance In vitro model systems should be evaluated in the context of age-related changes and should be benchmarked against human MSC data.

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Macromer density influences mesenchymal stem cell chondrogenesis and maturation in photocrosslinked hyaluronic acid hydrogels

Cited by 169 publications

References 43 publications

The pericellular environment regulates cytoskeletal development and the differentiation of mesenchymal stem cells and determines their response to hydrostatic pressure

The pericellular environment regulates cytoskeletal development and the differentiation of mesenchymal stem cells and determines their response to hydrostatic pressure

Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis

Cartilage Matrix Formation by Bovine Mesenchymal Stem Cells in Three-dimensional Culture Is Age-dependent

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