A new target for regenerative research

ALAMEDA, Calif.—Tissue regeneration is an area of interest to many companies in the industry, for applications from healing scars after surgery or burns to regeneration of hair cells in the ear canal for possibly restoring hearing. While a great deal of regenerative research is focused on stem cells, AgeX Therapeutics Inc., a subsidiary of BioTime Inc., has been looking at genes linked to regeneration, and recently shared new discoveries regarding one such gene, COX7A1. This work, a peer-reviewed study conducted by researchers at BioTime and AgeX in collaboration with Insilico Medicine, was published in Oncotarget.

The collaborators applied AI technology to evaluate genes that control natural tissue regeneration, and found that those genes are expressed differently early in development, when they still have the potential for regeneration, than they are later in life. Early in life, cells can regenerate from damage with no trace; as humans age, however, healing comes with scarring. As noted in the Oncotarget study: “In contrast to embryonic cells, fetal and adult-derived (F/A) cells often show reduced potential for organogenesis in vitro and epimorphic regeneration following injury in vivo [1]. The developmental timing of loss of epimorphosis potential cannot be fixed precisely, and likely varies with tissue type, however, one specific event - the embryonic-fetal transition (EFT) which occurs at eight weeks of human development (Carnegie Stage 23) [2], marks a loss of scarless skin regeneration in placental mammals [3].”

The issue, the authors note, is that “there are few molecular markers of the EFT to test its role in repressing epimorphic regeneration or the re-emergence of an embryonic phenotype in cancer.” Using Insilico's AI technology, the team applied “deep neural network ensembles trained on transcriptomic data” to find markers linked to EFT, which brought their attention to COX7A1, which “was up-regulated in post-EFT murine and human cells including adult stem cells, but was not expressed in pre-EFT pluripotent embryonic stem cells or their in vitro-derived progeny.”

“The embryonic-to-fetal transition (EFT) deciphered in this study is emerging as a wonderful new arena in which to explore the enhancement of regenerative capacity in old age, which is the core of AgeX’s mission,” said Dr. Aubrey de Grey, vice president of New Technology Discovery at AgeX. “The discovery of a subunit of the respiratory chain as a key EFT marker dovetails this research fascinatingly with age-related changes in mitochondrial function, which have long been a priority in the anti-aging field and in my own work.”

Beyond its link to EFT, COX7A1 is also tied to energy metabolism and cancer, which is perhaps unsurprising given cancer's uncontrolled replication and COX7A1's connection with cellular regeneration. The authors noted that “pre-EFT cell lines and cancer cell lines share many of the same morphological, proliferative and metabolic features,” and as such, further explored whether repression of COX7A1 could be a cancer marker as well. In testing its expression in osteosarcoma, liposarcoma and rhabdomyosarcoma, and comparing the expression levels to those of regular embryonic progenitors, they found COX7A1 to be minimally expressed or not expressed at all in a majority of the cancer cell lines. This held true when the team analyzed cancer cell lines for lung, breast, skin, kidney and liver cancer as well. In addition, the authors wrote that “Although the exact role of COX7A1 in the diverse metabolic pathways regulating malignancy is not yet clear, recent research reported by Mishra demonstrating that COX7A1 overexpression in the cancer cell line, A549, can induce apoptosis via an intrinsic mechanism (Caspase 9, 3 activation) [50] supports its potential role as a tumor suppressor.”

“It is rare to find genes implicated in tissue regeneration, let alone with abnormal expression in so many diverse cancer types such as those of the breast, lung, kidney, bone, and muscle,” Dr. Michael D. West, CEO of AgeX and co-CEO of BioTime, commented in a press release. “AgeX has certain rights to use the associated patent applications and to commercialize related therapeutic and diagnostic applications. Since we believe unlocking the natural ability of the human body to regenerate tissues afflicted with degenerative disease is a very large market opportunity, we are aggressively developing products using the technology.”

As for further investigation into this discovery, the authors write that more work is needed to evaluate “the extent to which highly glycolytic/OXPHOS-compromised COX7A1 deficient cells have increased regenerative ability, and the role of the phenotype in diverse aspects of tumor cell biology. The use of robust markers such as COX7A1 may facilitate these studies as well as a detailed examination of the epigenetic regulation of the EFT, thereby advancing our understanding of induced tissue regeneration (iTR) and oncogenesis.”