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. 2022 Mar 3;11(1):2-13.
doi: 10.1093/stcltm/szab005.

Improved MSC Minimal Criteria to Maximize Patient Safety: A Call to Embrace Tissue Factor and Hemocompatibility Assessment of MSC Products

Guido Moll  1 , James A Ankrum  2 , Scott D Olson  3 , Jan A Nolta  4
Affiliations

Improved MSC Minimal Criteria to Maximize Patient Safety: A Call to Embrace Tissue Factor and Hemocompatibility Assessment of MSC Products

Guido Moll et al. Stem Cells Transl Med. .

Abstract

The number of mesenchymal stromal/stem cell (MSC) therapeutics and types of clinical applications have greatly diversified during the past decade, including rapid growth of poorly regulated "Stem Cell Clinics" offering diverse "Unproven Stem Cell Interventions." This product diversification necessitates a critical evaluation of the reliance on the 2006 MSC minimal criteria to not only define MSC identity but characterize MSC suitability for intravascular administration. While high-quality MSC therapeutics have been safely administered intravascularly in well-controlled clinical trials, repeated case reports of mild-to-more-severe adverse events have been reported. These are most commonly related to thromboembolic complications upon infusion of highly procoagulant tissue factor (TF/CD142)-expressing MSC products. As TF/CD142 expression varies widely depending on the source and manufacturing process of the MSC product, additional clinical cell product characterization and guidelines are needed to ensure the safe use of MSC products. To minimize risk to patients receiving MSC therapy, we here propose to supplement the minimal criteria used for characterization of MSCs, to include criteria that assess the suitability of MSC products for intravascular use. If cell products are intended for intravascular delivery, which is true for half of all clinical applications involving MSCs, the effects of MSC on coagulation and hemocompatibility should be assessed and expression of TF/CD142 should be included as a phenotypic safety marker. This adjunct criterion will ensure both the identity of the MSCs as well as the safety of the MSCs has been vetted prior to intravascular delivery of MSC products.

Keywords: cellular therapy; coagulation; coagulopathy; hemocompatibility; mesenchymal stromal/stem cells (MSCs); product diversification; safety and efficacy; thromboembolism; tissue factor/CD142/Factor III/F3; tissue source.

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Figures

Graphical Abstract
Graphical Abstract
A broad spectrum of oversight impacts on MSC product safety in patients. We here outline the necessary steps toward integration of highly procoagulant tissue factor (TF/CD142) and hemocompatibility assessment of diversified intravascular MSC products as a new safety criterion into the existing MSC minimal criteria. Regulatory authorities and international societies should undertake coordinated efforts to update the already established guidelines.
Figure 1.
Figure 1.
A broad spectrum of oversight impacts on mesenchymal stromal/stem cell (MSC) product safety in patients. While most respected academic centers and professional larger-scale manufacturers and sponsors of well-regulated clinical trials rely on quality systems that minimize the potential of adverse events from intravascular administration of procoagulant tissue factor (TF/CD142) expressing MSC therapeutics (right panel) (eg, submission of an investigational new drug (IND) application to the FDA), there exist hundreds of poorly regulated and poorly controlled “Stem Cell Clinics” internationally, which operate in an environment of lax medical regulations, thus risking potential harm of patients (left panel)., Potential adverse events from intravascular administration include disturbances of hemostatic parameters, which can cause micro-/macro-thrombosis and (pulmonary) thromboembolism, vessel occlusion, and tissue ischemia, that can lead to disability and may potentially end fatal under inappropriate patient supervision.,
Figure 2.
Figure 2.
Increasing mesenchymal stromal/stem cell (MSC) product diversification necessitates TF/CD142 screening and hemocompatibility assessment for intravascular MSC applications. (A) MSC products have greatly diversified in the past decade, for example, the tissue source that they are derived from, with bone marrow (BM), perinatal tissue (PT), and adipose tissue (AT) being the most frequent sources, which is decisive for the optimal mode of clinical delivery to patients, for example, intravascular (IV) infusion versus intramuscular or subdermal (IM/SD) injection, or intratracheal (IT) delivery,; and (B) Product qualification has shown large differences in expression of procoagulant tissue factor (TF/CD142) between different products (BM lowest, PT intermediate, and AT highest), which impacts on the cells’ hemocompatibility properties in vitro and in vivo, and may lead to adverse thrombotic reactions if left unchecked before clinical application. Abbreviations: complement factors C3, C5, C3b, iC3b, C3a, and C5a, and regulatory molecules: membrane cofactor protein (MCP/CD46), decay-accelerating factor (DAF/CD55), protectin (CD59), and factor H and I; coagulation factors I-XII (FI-XII), including their activated intermediates (eg, FXIIa) and regulators antithrombin (AT), tissue factor pathway inhibitor (TFPI) and prostacyclin (PGI2), and instant blood-mediated inflammatory reaction (IBMIR).
Figure 3.
Figure 3.
Improved clinical guidelines and minimal criteria for the characterization of diversified mesenchymal stromal/stem cell (MSC) products to include TF/CD142 and hemocompatibility assessment. (A) Clinical need: representative images on blood clot formation upon in vitro exposure of different types of tissue factor (TF/CD142) expressing MSC products to non-anticoagulated human blood from blood type AB and O donors, with comparison of different types of MSC products resuspended in buffer containing 5% human blood type AB plasma (ABP) versus blood supplementation with 5% ABP buffer only, documenting that the blood from O donors containing higher levels of anti-A/B antibodies reacts stronger to therapeutic cells loaded with A/B antigen than the blood from AB donors containing no anti-A/B antibodies, as visualized by stronger clot formation after a 30 minutes cell exposure period to the blood in the Chandler loop model, however, the decisive factor appears to be the tissue source the cells are derived from, with weaker reactions to similar doses (15 000 cells/mL blood) of bone marrow (BM)-derived BM-MSCs than perinatal tissue (PT)-derived PT-MSCs, or human skin fibroblasts used as positive controls. (B) Historical timeline of integrating hemocompatibility testing of cellular therapies into clinical practice, to mitigate the risk for thromboembolism due to triggering of the instant blood-mediated inflammatory reaction (IBMIR) upon intravascular (IV) delivery of MSC products, with the establishment of first “MSC minimal criteria” in 2006, with suggested updates on “Immunopotency” and “Hemocompatibility” in 2016 and 2021, respectively, with more updated criteria comprising cell identity, activity/potency, and safety in 2021.
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References

    1. Caplan AI. What’s in a name? Tissue Eng Part A. 2010;16(8):2415-2417. - PubMed
    1. Bianco P, Cao X, Frenette PS, et al. . The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19(1):35-42. - PMC - PubMed
    1. Sacchetti B, Funari A, Remoli C, et al. . No identical “mesenchymal stem cells” at different times and sites: human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Rep. 2016;6(6):897-913. - PMC - PubMed
    1. Caplan AI. Mesenchymal stem cells: time to change the name! Stem Cells Transl Med. 2017;6(6):1445-1451. - PMC - PubMed
    1. Boregowda SV, Booker CN, Phinney DG.. Mesenchymal stem cells: the moniker fits the science. Stem Cells. 2018;36(1):7-10. - PubMed

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