**Acknowledgements**

model with these astrocyte transplants [155]. These data show that astrocytes possess thera‐ peutic potential to address important neurological diseases. To build upon the ideas set forth by these transplant studies, one could ask how could we target the endogenous astrocytes to achieve similar outcomes? While the answer to this important question is likely complex, if our own ideas on the origins of astrocyte heterogeneity are valid, then select targeting of ECM-Astrocyte communication may be one approach to try. For instance, targeting of the β1 integrin using the RGD peptide has been shown to prevent astrogliosis in the injured spinal cord and improve functional recovery [156]. With an advanced understanding on how the ECM controls, or at the very least influences, the function of astrocytes *in situ* during brain injury or

In the future, we suggest that technical approaches are now available to advance this line of investigation in ways not previously feasible. For instance, cataloging astrocyte diversity using single-cell laser-capture sequencing may be expected to identify unique markers to distinguish different subtypes of astrocytes from tissues. This approach would also allow for the important distinction of acquiring astrocytes that are spatially and temporally associated with specific types of neural injury [157]. A similar approach has recently been used to identify markers of reactive astrocytes. Results from these types of future investigations should enable us to delve deeper into the complexity of astrocyte biology and better understand the nature and function of these cells as they maintain the CNS and react and participate in neurological disease states.

**Figure 2.** Hypothesized model of influence of ECM on innate and acquired astrocyte heterogeneity. Depicted are two different astrocytes, labeled A and B which have been positioned along the X-axis to reflect innate heterogeneity on the basis of their location within the central nervous system (CNS). In response to a stimulus (labeled A' and B', respec‐ tively), the innate heterogeneity impacts the reactivity, as depicted as different locations along the Y-axis. Lastly, with chronic stimulation, these two distinct cells develop distinct long-term phenotypes, labeled A" and B", where the in‐ nate heterogeneity results in different outcomes to the long-term stimulation. Whereas A depicted as a smaller sphere lower on the Y axis may become chronically less active, perhaps related to development of an astrocyte scar, the other astrocyte labeled B" with chronic stimulation adapts to become a more active, perhaps physiologically adapted, phe‐

notype contributing to neuropathology in disease.

disease, we may be able to target and promote brain recovery and repair.

128 Composition and Function of the Extracellular Matrix in the Human Body

We thank Alexandra Nicaise for her helpful feedback on this manuscript. CW and SJC were supported in part by grants from the National Multiple Sclerosis Society (USA) (Grant# RG5001-A-3, to SJC) and the National Institutes of Health (Grant# NS087578, to SJC).
