Two mammalian receptor tyrosine kinases (DDR1 and DDR2) have extracellular domains closely related to a D. discoideum lectin, discoidin, required for cell aggregation. Here, we show that the mammalian DDR receptors bind and are activated by specific types of collagen. Stimulation of DDR receptor tyrosine kinase activity requires the native triple-helical structure of collagen and occurs over an extended period of time. Collagen activation of DDR1 induces phosphorylation of a docking site for the Shc phosphotyrosine binding domain, whose presence is controlled by alternative splicing. Activation of DDR2 by collagen results in the up-regulation of matrix metalloproteinase-1 expression. These results suggest that the discoidin-related DDR tyrosine kinases are novel collagen receptors with the potential to control cellular responses to the extracellular matrix.

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

Inorganic nanoparticles are frequently engineered with an organic surface coating to improve their physicochemical properties, and it is well known that their colloidal properties may change upon internalization by cells. While the stability of such nanoparticles is typically assayed in simple in vitro tests, their stability in a mammalian organism remains unknown. Here, we show that firmly grafted polymer shells around gold nanoparticles may degrade when injected into rats. We synthesized monodisperse radioactively labelled gold nanoparticles ((198)Au) and engineered an (111)In-labelled polymer shell around them. Upon intravenous injection into rats, quantitative biodistribution analyses performed independently for (198)Au and (111)In showed partial removal of the polymer shell in vivo. While (198)Au accumulates mostly in the liver, part of the (111)In shows a non-particulate biodistribution similar to intravenous injection of chelated (111)In. Further in vitro studies suggest that degradation of the polymer shell is caused by proteolytic enzymes in the liver. Our results show that even nanoparticles with high colloidal stability can change their physicochemical properties in vivo.

Various types of collagen have been identified as potential ligands for the two mammalian discoidin domain receptor tyrosine kinases, DDR1 and DDR2. Here, we used a recombinant fusion protein between the extracellular domain of DDR1 and alkaline phosphatase to detect specific receptor binding sites during mouse development. Major sites of DDR1-binding activity, indicative of ligand expression, were found in skeletal bones, the skin, and the urogenital tract. Ligand expression in the uterus during implantation and in the mammary gland during pregnancy colocalized with the expression of the DDR1 receptor. The generation of DDR1-null mice by gene targeting yielded homozygous mutant animals that were viable but smaller in size than control littermates. The majority of mutant females were unable to bear offspring due to a lack of proper blastocyst implantation into the uterine wall. When implantation did occur, the mutant females were unable to lactate. Histological analysis showed that the alveolar epithelium failed to secrete milk proteins into the lumen of the mammary gland. The lactational defect appears to be caused by hyperproliferation and abnormal branching of mammary ducts. These results suggest that DDR1 is a key mediator of the stromal-epithelial interaction during ductal morphogenesis in the mammary gland.Membrane-bound receptors with intrinsic protein tyrosine kinase activity are designed to sense a variety of extracellular stimuli. Activated receptor tyrosine kinases (RTKs) initiate signaling pathways leading to proliferation, differentiation, metabolism, survival, or cell death. It has been estimated that mammalian cells contain at least 150 genes coding for protein tyrosine kinases (13).The two discoidin domain receptors, DDR1 and DDR2, represent a subfamily of RTKs and are expressed in a variety of mouse and human tissues (34). In the N-terminal part of the extracellular region, DDRs have a region related to the Dictyostelium discoideum protein discoidin. During cell aggregation of Dictyostelium, discoidin is secreted and functions as a lectin. In higher organisms, discoidin domains have been recognized in a variety of membrane-bound and secreted proteins, such as the neuropilins or blood clotting factors V and VIII (4). However, it still remains to be shown that mammalian discoidin domains have a binding affinity to carbohydrates.Various types of collagen have been identified as potential ligands capable of activating both DDRs. Whereas DDR1 autophosphorylation is induced by all collagens so far tested (type I to type VI), DDR2 is only activated by fibrillar collagens, in particular by collagen type I and type III (30,33). In contrast to most other RTKs, DDR activation by collagen follows slow kinetics and can take up to 18 h to reach maximal kinase activity. While it is apparent that collagen needs to be in its native, triple-helix configuration to activate DDR, the binding epitopes for the DDR extracellular domain on a collagen molecule and the significance of the discoidin region in collagen bind...

Key Points Epigenetics and in vivo behavior can distinguish MSCs from different sources. BM-derived MSCs form a hematopoietic niche via a vascularized cartilage intermediate.