by
Donald G. Phinney, PhD
Senior Editor
Department of Molecular Medicine
UF Scripps Biomedical Research
Jupiter, FL, USA
I want to extend my gratitude to all returning Editorial Board members and welcome new member to the journal. I look forward to many productive interactions with all members in 2023. I also want to welcome Dr. Susan Prockop, MD as an Associate Editor. Susan brings a wealth of experience in hematology, oncology, cell and gene therapy, and post-transplant complications of graft vs host disease and infection. She has replaced Dr. Luis Ortiz, MD who during his tenure managed numerous reviews including many clinical papers and offered guidance and advice on many issues that benefited the journal and myself as Senior Editor. Many thanks to Luis, who will continue to serve the journal as a member of the Editorial Board.
In this issue of Cytotherapy Corner, I want to highlight a manuscript in the February 2023 issue by Shuster-Hyman et al., that tracks the biodistribution and fate of a single intravenous dose of human umbilical cord perivascular cells (HUCPVCs), which are a rich source of MSCs, in naïve mice or after challenge with LPS. As expected, LPS induced a systemic inflammatory response and neuro-inflammation, both of which were abrogated by infusion of HUCPVCs. While HUCPVCs rapidly localized to the lungs, their levels did not differ significantly in naïve vs LPS treated mice when measured at 5 min or 24h post-injection. Therefore, localization of HUCVVCs to lung tissue did not appear to reflect active homing in response to inflammation. The authors also detected cleaved caspase 3 in lung tissue, a marker of cellular apoptosis, but levels also did not significantly differ between control and LPS treated mice. Additionally, HUCPVC infusion induced significant infiltration of neutrophils and CD206 expressing macrophages into lung tissue, and while neutrophil levels were elevated in response to LPS treatment, it had minimal impacts on macrophage levels. Therefore, while these results support the pulmonary first pass effect model of MSC action wherein efferocytosis of lung resident MSCs induce system wide therapeutic impacts, many unanswered questions remain. For example, this like many studies employed a single dose of HUPVCs. Therefore, whether infused MSCS exhibit dose dependent impacts on macrophage polarization or if a threshold of cellular apoptosis is needed to induce polarization remains indeterminate. Since there is no consensus on a “therapeutic” dose for MSCs, addressing this question may inform clinical practices. Also, while studies have shown that macrophage ablation nullifies MSC-mediated impacts in preclinical models of sepsis and graft vs host disease, it is unclear if infusion of polarized macrophages can recapitulate MSC-mediated impacts, and what degree of polarization is required in vivo to produce these effects. Lastly, while MSCs are not drugs, their therapeutic index is indeterminate, and since some pharmacodynamic impacts may be detrimental including triggering of blood-mediated inflammatory reactions, understanding dose dependent impacts is critically important.
In the March Issue, I want to draw attention to a Gene Therapy Mini-Series that includes four papers describing advances and challenges associated with gene editing approaches and the use of AAV vectors for targeted delivery of therapeutic genes. Two manuscripts by Bhoopalan et al., and Ugalde et al., provide an overview of gene editing technologies, their application to hematopoietic stem/progenitor cells for treating congenital blood disorders and inherited bone marrow failure syndromes, and challenges associated with implementation of these technologies. The manuscript by Lahr et al., discusses current advances in base editing technologies with the ability to perform single base conversions, and their clinical applications in cancer immunotherapy and gene therapy. Lastly, the manuscript by Szumska and Grimm review several technologies that provide a means to identify clinically relevant AAV capsids including barcoding and high-throughput screening of individual AAV variants or entire capsid libraries, selection of transduction-competent AAV vectors, enrichment of expression competent AAV variants, and high-resolution stratification of focused AAV capsid libraries at the single-cell level, which aim to expand and refine viral targeting for a therapeutic intent.
Happy reading.
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