The below is my opinion and may not accurately reflect the intended position. Portions had to be retyped which may lead to inaccuracies quotes.
The article appears to be led by the Texas Heart Institute, given the number of authors credited versus one from quite a few other universities and the national heart, lung and blood institute. Inevitably you will see a Maya Pomroy video in the next few weeks with Emerson explaining the findings with a bit more colour and depth.
The main theme was recommendation of common nomenclature and frameworks to move forward in the industry as it is hard to compare/leverage other studies and explain the inconsistent results. They note the inherent complexity in comparing stem cells (Bone marrow to placenta), but also the change in cells over time. This shows how early we are in the journey but also a way forward to drive success. The points I will raise below were some of the insights that I found interesting.
An interesting quote worth a read “The cell populations used in cardiovascular studies, contain only a small fraction of true stem cells but are instead relatively enriched with “functionally defined” cells that do not meet the criteria to be considered stem cells. An exception is one of the most promising cell types in clinical use - mesenchymal cells - that instead meet the developmental biology definition of multipotent stem cells, as they can differentiate down multiple pathways giving rise to mesodermal and endodermis cell types.”
Stem Cell Differentiation
The FDA raised quite a few concerns in the GvHD filing and the paper in my view agrees with concern but discusses ways forward that IMO should help in the OTAT meeting.
“There is mounting evidence that MSC from different tissue sources have distinct molecular phenotypes, both in terms of
surface markers and secretome components”
“For example, Billing et al identified approximately 2,500 significantly differentially expressed genes when comparing human BM-derived and embryonic stem cell (ESC)-derived MSCs using RNA sequencing and 40-200 proteins using mass spectrometry-based proteomics”
Recommendations
The use of CD surface markers to “determine lineage and differentiation state” (e.g. CD34+). They included a table with their CD markers for different types of stem cells.
Cell Assays “ The colony forming unit (CFU) assay is a hematopoietic functional assay, which is often used to measure the function or potency of hematopoietic progenitors present in the peripheral blood or bone marrow.
The phenotype of cells in the final product should be assessed (e.g., by polychromatic flow cytometry) and reported, because the expression of markers may change in culture.
“Every time a preclinical or clinical study is performed, the cell type should be characterized in vitro to include the above features (CD panel, tissue source) plus the cell age (population doublings and doubling time in hours).“
IMO The above supports why tweaks in the manufacturing process drive different clinical results (e.g. Mesoblast vs Osiris). It also infers the challenges, another part quoting the different amount of red blood cells could change the efficacy.
iPSCs
“induced pluripotent stem cells (iPSCs) – to differentiate into several cell types opened a new avenue for the treatment of several diseases. However, despite improvements in the reprogramming process [52] and clinical-grade large scale cell expansion [53], the use of these cells is limited by safety concerns, such as genetic instability, epigenetic abnormalities, potential for teratoma formation [54], and immaturity of the subsequent cell product.”
“the lack of consensus between the societies with respect to pluripotent stem cell purity standards must be addressed to effectively and safely use these cells as a clinical product.“
Final thoughts
There was a very interesting quote that might explain why we underachieved on COVID.
“Importantly, an association between patient’s age and proliferative potency of these cells has been reported [15]. In addition, abnormal function of stromal precursor cells has been related to several diseases, invalidating the use of these cells for cell therapy [16].”
They recommend dropping stem cell therapy with “cardiovascular cell-based therapy” or simply “cell-based therapy” or “cell therapy”.
“Finally, the phrase “regenerative therapy” or “regenerative cardiology” should be avoided, because cell therapy does not regenerate myocardium but more accurately repairs damaged tissue, possibly via anti-inflammatory, anti-fibrotic, and/or anti-apoptotic effects [20].“
Hopefully this is helpful for the few people that were interested, any questions let me know and happy to share other sections. It was 41 pages so there is a lot that was omitted, but I am sure Emerson or the THI will provide a much better overview in the future. If anyone else read the article I would love to hear what you thought.
(20min delay)