Title of proposed idea: Exploring the Extracellular Space
Nominator: NIH Institutes/Centers
Major obstacle/challenge to overcome: The Extracellular Space (ES) occupies the space between cells, outside their plasma membrane. The ES consists of the extracellular matrix (ECM) and the interstitial fluid. It is filled with an ionic solution of mainly NaCl and contains a complex cocktail of molecules necessary for: 1) cellular survival (that includes glucose, amino acids, lipids, etc.), 2) tissue integrity (involving macromolecules such as collagen, lipoproteins, proteoglycans, glycoproteins, etc.), 3) physiological function of cells and tissues (such as growth factors, cytokines, hormones, neurotransmitters, metabolites, cholesterol, protease, protease inhibitors, etc.), and 4) transducing mechanical strain for proper tissue function. The volume, pH and composition of the ES can differ significantly between tissues and are altered dramatically upon pathological processes. Although there has been much focus in tools and technology development for the investigation of intracellular processes, proteins, and molecules, to date little attention has been devoted to the ES and how the cellular microenvironment contributes to health and disease.
Emerging scientific opportunity ripe for Common Fund investment: Emerging tools and technologies already funded by the NIH Common Fund and other agencies that are being used to investigate and interrogate cellular processes will greatly accelerate understanding and control of the extracellular milieu in health and disease. The convergence of the indicated fields below and the collaborative efforts of practitioners from these various disciplines will greatly advance our knowledge base of ES.
- Single cell analysis
- Molecular probes
- iPSCs generation and differentiation
NIH Common Fund investment would galvanize efforts towards a multidisciplinary approach towards determining the influence of the ES in health and disease.
Common Fund investment that could accelerate scientific progress in this field: The NIH has some ongoing efforts in investigating the biology of extracellular space. The majority of these activities are focused on the role of ECM stiffness – a feature found in cancer and most diseases. A more synergistic approach catalyzed by Common Fund investments and utilizing cutting edge technologies as described above will provide a more global and comprehensive understanding of ES physiology and function and how these are perturbed in disease. In addition, Common Fund investments will also provide impetus for the less appreciated information on the flow of gradients and soluble factors in tissue microenvironment. While we know of signaling of many growth factors and cytokines, we know very little how these molecules are organized in the ES space – after protease digestion for example, or during cell migration or morphogenesis. Moreover Common Fund investments will open up new areas of research on the exciting and novel roles of exosomes produced by cells of different origins. Recent findings indicate that tumor cells (and likely various other cell types), much like immune cells, also secrete or produce exosomes which are loaded with miRNA and other RNA species, as well as constituted activated signaling molecules, such as AKT, which can through paracrine fashion modulate other cells. There is some emerging evidence that the exosome cargo (e.g. miRNA) is actually released and picked by neighboring cells. Exosome-mediated transfer of mRNA and miRNA is a novel mechanism of genetic exchange. Moreover exosomal load assessment and exosomal molecular profiling, such as miRNA signatures, can serve as a source of diagnostic biomarkers that hold great promise for disease detection and monitoring.
Potential impact of Common Fund investment: A thorough understanding of the cellular milieu can lead to breakthroughs in
- understanding and control of homeostasis
- intercellular communication
- paracrine and autocrine functions
- transport of nutrients, factors, metabolites, and degradation products to and from cells
- establishment of resting potential of cells
- tumor growth and metastasis
- tissue injury and repair
- regenerative medicine
- drug delivery, since access of soluble drugs to cells in tissues is mediated by ES, and ECM macromolecules serve and can be exploited as attachment sites for various pharmacological compounds
- drug targeting and development
- biomarkers of disease
- cell re-programming
- cellular mimics of disease
- elucidating disease processes by bridging the gap between intracellular and extracellular events, and the crosstalk that takes place