Collagen Functional Hydrogel
While the ECM is composed of around 300 proteins, proteoglycans (heparan sulfate), glycoproteins (laminin and fibronectin), and collagen are the most common components1. The collagen superfamily consists of 28 different isoforms in vertebrates8. Collagens consist of three polypeptide chains, referred to as α chains8. Different α chains are subcategorized and given a numerical value. Moreover, many collagen isoforms are proteolytically cleavable, which can lead to the production of fragments with exposed, bioactive, cryptic binding sites11. Collagen I is the most abundantly expressed ECM protein and is regularly used in cell studies12. Cells readily bind to collagen matrices and are shown to survive at high rates. Collagen promotes attachment of cells from multiple tissues, including cancer13, skin14, eye15, and muscle16. Collagens bind different receptor families, including integrins, receptor tyrosine kinases, leukocyte receptor complex, and mannose receptor family43. Integrin receptors are highly expressed adhesion receptors that, upon ECM binding, recruit a variety of adhesion scaffold, signaling, and stretch gated proteins to initiate and stabilize adhesion complexes44, 45. Integrin based adhesions regulate intracellular signaling, cell morphology, and migration, and may be important for cell survival. Integrin receptors are heterodimers consisting of α (18 in humans) and ß (8 in humans) subunits46. Collagen has been shown to bind four different integrin heterodimers (α1β1, α2β1, α10β1, and α11β1)43. Among these, collagen I binds α1β1 and α2β1, with a particular affinity for α2β143. The bioactive motif underlying collagen I and α2β1 interaction was discovered by Knight and colleagues to be GFOGER, and has subsequently been used in a variety of studies7. Being that this motif underlies cell-collagen matrices binding, hydrogels modified with covalently bound GFOGER, VitroGel COL, have been developed for cell culture studies.
The field of cancer biology has perhaps most significantly utilized 3D collagen matrices. Collagen gels give cancer researchers a great cell culture system to study cancer cell clustering, invasion, and migration. Upon attachment, collagen matrices support the proliferation of many different cancer cell lines13,17,18. This process is dependent upon the ability of cells to spread and change morphology. Cell spreading has been observed in collagen matrices with different cancer types, including breast cancer. Specifically, MCF-7 cells, a breast cancer cell line, were shown to have spread morphologies in 3D collagen gels, which ultimately lead to increased proliferation, likely due to increased expression of matrix metalloproteases (MMPs)17. In vivo, cancer cells, and cancer-associated fibroblasts, release MMPs, and ECM molecules, to remodel the local environment. Due to the fibril structure of collagen, cancer facilitated remodeling can create fibril “tracks” upon which cancer cells can migrate1. Also, MMP release can breakdown ECM barriers, allowing metastatic cancer cells to invade and disseminate. This phenomenon has also been observed and investigated in 3D collagen. Specifically, cancer cell lines have been shown to upregulate MMPs in collagen17–20, leading to increased invasion18–22 and migration19,22,23, likely due to ECM remodeling. While studies have illustrated the importance of MMP activity in promoting cancer cell growth and metastasis, few studies have examined the effect of both collagen binding and ECM remodeling using modifiable hydrogels. However, using a modified hydrogel containing GFOGER, as an adhesive peptide, and MMP target substrates, Mhanna et. al. (2014) found human mesenchymal stem cells spread and were highly proliferative relative to non-degradable hydrogels. Thus, these effects can be further studied in other cell types, such as cancer cells, using a combination of VitroGel COL and VitroGel GFOGER. Overall, studies utilizing 3D collagen gels have expanded how we can examine cancer progression.
In addition to cancer biology, 3D collagen gels are powerful tools to study tissue development. Using collagen gels allows scientists to examine the mechanisms of development from studying individual cell morphological changes to tissue engineering. Individual cell morphological changes, such as cell spreading, may be investigated in real-time in collagen matrices. Collagen induces cell spreading of different cell types, such as fibroblasts24, lung fibroblasts16, corneal endothelial cells15, hepatocytes25, myoblasts16, and aortic endothelial cells24,26. Moreover, cell spreading and integrin-mediated signaling have been shown to control cell differentiation27–31, which has been extensively studied in 3D collagen. For instance, osteogenic differentiation of human32 and mouse33 bone marrow-derived mesenchymal stem cells was observed in 3D collagen gels. Differentiation was also detected with muscle cells, where collagen matrices induced mature myoblast differentiation and the subsequent formation of myotubes34,35. Collagen also supports the differentiation of embryonic stem cells into mature neurons36, further illustrating the many different cell types that may be examined using collagen gels.
Similar molecular processes are conserved during cell migration and neurite outgrowth, including integrin-mediated adhesions. Consequently, collagen matrices are a robust cell culture system used to study cell mobility and neurite extension. In fact, cells migrate rapidly on collagen19,22,23.Additionally, neurite extension in 3D collagen gels has been shown with human37, chick38,39, and rat40–42 neurons. Furthermore, the mechanical properties of collagen strongly control neurite extension, as cortical and peripheral neurites often extend more rapidly in soft collagen relative to rigid37–39. Conversely, Nichol and colleagues found human motor neurons extend longer neurites in more rigid collagen gels37.Taken together, these data further demonstrate the advantages of collagen gels in studying different developmental processes in a variety of tissue.
As stated above, GFOGER can act as a functionalized ligand for cells expressing integrin receptors to bind and undergo subsequent morphological changes and migration. Similar to other ECM derived small peptides, e.g. RGD, YIGSR, or IKVAV, GFOGER is most extensively used as an adhesive ligand to test cellular processes and promote tissue engineering for healthy and disease cells48. GFOGER has most widely been used in 3D hydrogels to examine osteogenic differentiation and bone regeneration49–56, as well as cancer cell behavior57–61. In multiple studies, the employment of 3D hydrogels containing GFOGER has been shown to drive differentiation of bone marrow stromal or mesenchymal cells into mature osteogenic cells51,52,55,62–64 with the ability to remodel the ECM53. More importantly, the effects of GFOGER on osteogenic differentiation have enabled researchers to utilize GFOGER incorporated hydrogels to repair bone in vivo. Injectable GFOGER hydrogels, in conjunction with bone morphogenic protein 2, were found to drive greater bone repair in mouse bone defects than hydrogels containing RGD62. In another study, GFOGER was immobilized onto polycaprolactone scaffolds and implanted into rats with bone injuries50. Implanted GFOGER coated polycaprolactone scaffolds promoted bone regeneration as measured by an increase in bone mass. The bone regenerative effects of GFOGER have been additionally observed in vivo with other materials, including titanium51, poly(ethylene glycol) (PEG)54, and hydroxyapatite55. Besides osteogenesis, GFOGER supports the development of many other tissue types. For example, GFOGER may be used as an adhesive substratum for liver65, muscle58, neural66, and vascular67 cells. In addition, similar to RGD, GFOGER has been utilized to support adhesion, proliferation, and differentiation of stem cells68. Encapsulating stem cells proliferated and differentiated into chondrogenic cells that secreted cartilage-specific ECM. Overall, these studies demonstrate the use of GFOGER modified biomaterials as a promising tool to study cell adhesion, differentiation, and regeneration, among other phenomena.
As stated above, ECM and specifically collagen, remodeling is a critical step in cancer progression. Therefore, VitroGel COL, which contains GFOGER provides a robust platform to study myriad cancer cell behaviors, including adhesion, proliferation and cell cluster growth, invasion, and migration. Similar to RGD and native collagen, GFOGER has been shown to act as an effective adhesive substratum for different types of cancer cells, such as breast57, fibrosarcoma58,59, glioma60, and prostate61. The GFOGER mediated effects on cancer cell adhesion were shown to be integrin-dependent58,60. Furthermore, adhesion allows for cancer cell aggregation and cluster growth, a cell culture model for tumor growth. Sawicki and colleagues demonstrated GFOGER dependent adhesion and subsequent cluster growth of two independent breast cancer cell lines, MDA-MB-231 and T47D57. Likewise, GFOGER incorporated hydrogels promoted an invasive morphology, migration, and clustering of PC3 cells, a metastatic prostate cancer cell line61. These data further illustrate the ability of GFOGER to act similarly to native collagen and promote cell behaviors.
Cell Type Behavior Reference Table for VitroGel COL
|Bovine bone marrow stromal cells||Increased cell spreading and osteocalcin expression|
|Human bone||Increased cell spreading, proliferation, and collagen II production|
|marrow mesenchymal stem cells|
|Rat bone marrow stromal cells||Increased cell adhesion and osteoblast differentiation|
|Human bone marrow-derived mesenchymal stem cells||Promoted calcium deposition and chondrogenic/|
|Mouse bone marrow stromal cells||Supports osteogenesis|
|Breast MDA-MB-231||Increased cell cluster size and spreading|
|Breast T47D||Increased cell cluster size|
|Breast T47D||Promoted force dependent tubule formation|
|Breast MCF-7||Increased cell proliferation, morphological changes, MMP expression, and angiogenesis|
|Co-culture of liver carcinoma HepG2 and stromal fibroblasts 3T3-J2||Increased cell viability, growth, and drug resistance|
|Fibrosarcoma HT1080||Support cell infiltration and growth|
|Fibrosarcoma HT1080||Promoted integrin dependent cell adhesion|
|Fibrosarcoma HT1080||Promoted cell adhesion|
|Glioma RuGli||Promoted integrin dependent cell adhesion|
|Glioma U87-MG||Cell migration dependent on mechanical force|
|Prostate PC3||Increased cell invasion, migration, and spheroid metabolic activity|
|Human primary breast||Promoted cell invasion, migration, and dissemination|
|Melanoma B16F10||Increased cell migration, invasion, and MMP release|
|Ovarian OVCA429||MMP dependent cell invasion|
|Prostate LNCaP||Supported cell proliferation and increased prostate-specific antigen release|
|Prostate PC3||Supported cell proliferation and reduced MMP release|
|Lung fibroblasts HFL1 (CCL153)||Promoted cell proliferation and spindle morphology|
|Human lung cancer associated fibroblasts||Increased smooth muscle actin and substrata contractility|
|Lung fibroblasts MCR-5||Promoted NGF-mediated substrata contraction|
|Human myoblasts||Promoted cell adhesion, alignment along fiber, and myotube formation|
|Mouse myoblast C2C12||Promote integrin dependent cell adhesion|
|Myoblasts C2C12||Promoted formation of myotubes and myotendinous|
|Myoblasts C2C12||Promote cell proliferation, differentiation, and myotube formation|
|Myoblasts C25Cl48||Promote cell proliferation, differentiation, and myotube formation|
|Human neural stem/progenitor cells||Promoted cell attachment|
|Chick dorsal root ganglion||*Increased neurite length on soft|
|Chick dorsal root ganglion||*Increased neurite outgrowth toward soft|
|Human motor neurons||*Increased neurite length on rigid|
|Human forebrain neurons||*Increased neurite length on soft|
|Neural PC12||Increased neurite length|
|Rat cortical neurons||Increased neuronal viability and neurite length|
|Rat dorsal root ganglion||Promoted axon outgrowth|
|Rat dorsal root ganglion||Promoted neurite outgrowth|
|Rat spinal cord section||Promoted neurite outgrowth|
|Human mesenchymal stem cells||Promoted cell adhesion, spreading, viability, and osteoblast differentiation|
|Human mesenchymal stem cells||Promoted chondrogenic differentiation|
|Human mesenchymal stem cells||Increased cell migration, proliferation, and osteogenic differentiation|
|Human mesenchymal stem cells||Promoted cell attachment and tenogenic differentiation|
|Human mesenchymal stem cells||Promoted cell proliferation|
|Mouse embryonic stem cells||Supported neuronal differentiation and neurite outgrowth|
|Bovine aortic endothelial cells||Promoted cell spreading along fiber|
|Bovine aortic endothelial cells||Increased cell spreading on rigid|
|Bovine capillary endothelial cells||Formation of capillary like networks|
|Human umbilical vein endothelial cells||Increased VEGF dependent vascularization|
|Human umbilical vein endothelial cells||Promoted cell adhesion, spreading and supported increased VEGF dependent migration|
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