Matrix Biology’s August 2022 edition includes a report entitled “Matrix-bound Cyr61/CCN1 is required to retain the properties of the bone marrow mesenchymal stem cell niche but is depleted with aging”. The report is written by StemBioSys scientific advisor Milos Marinkovic, Ph.D., Assistant Professor in the Department of Comprehensive Dentistry at University of Texas Health at San Antonio. It is based on studies conducted with a team of scientists including StemBioSys CTO Travis Block, Ph.D. and StemBioSys founder and scientific advisor Xiao-Dong Chen, M.D., Ph.D., Professor in the Department of Comprehensive Dentistry at University of Texas Health at San Antonio.

The team produced extracellular matrices (ECMs) from bone marrow (BM) stromal cells harvested from young (ages 25 and younger) and aging (ages 60 and older) donors. When young BM mesenchymal stem cells (MSCs) were cultured on elderly BM-ECMs, they showed marked deterioration in their ability to respond to osteogenic growth factors, but increased responsiveness to adipogenic differentiation. Notably, the aging BM-ECM was also found to harbor significant differences in architectural and mechanical properties relative to young.

Based on these findings, the team carried out tests to determine which ECM components were responsible for the differences in cell behavior caused by the aging niche.

CCN1 is Crucial

ECM proteomics analysis revealed that the matricellular protein CCN1 (also referred to as Cyr61) was detectable in young ECMs, but absent in elderly ECMs. Further validation confirmed that CCN1 production decreases with age. 

The team hypothesized that a potential aging-induced decrease in ECM-bound CCN1 was the reason for the loss of BM-MSC properties within the stem cell niche. Additional testing comparing young and elderly mice indicated that lower amounts of CCN1 in the latter correlated to low bone mineral density, supporting their hypothesis.

Up-Regulating CCN1 into the Niche

The next step in the study was to identify potential methods of modifying the incorporation of CCN1 in the cell-derived BM-ECM. The team first added CCN1 exogenously to the matrix, but found this method to be unsuccessful. After further testing, another method proved more effective: genetic modification during the synthesis of the matrix. “We found that the way to change the levels of incorporation into the matrix [was to introduce] production of the protein at the gene level,” Dr. Marinkovic notes. “We used an adenoviral vector - a virus that carries the CCN1 gene of interest, and we infected the cells with this viral vector [and caused] them to overexpress.” Essentially, the team added a step to the process, prior to producing the matrix: transfecting the cells to increase their baseline expression of the CCN1 protein.

Next Steps

“What [these findings] suggest is that there may be a therapeutic application [with regard to] restoring or repairing the degenerated or damaged stem cell niche,” Dr. Marinkovic says, before providing some additional context. “[With] diseases like cancer, or even in aging in general, these niches - physical 3D environments in which the stem cells in a given tissue reside - start to change. These niches are important because they actually tell the stem cells what to do. We're still at the very beginning of trying to understand, on a tissue by tissue basis, how these niches change during disease, during cancer, during aging.”

The use of StemBioSys matrices helps scientists to recreate these niches outside of the body so that they can more easily study the changes that occur - and use their knowledge of these changes to drive further advancements in cell repair and regeneration.