Concise Review: Quantitative Detection and Modeling the In Vivo Kinetics of Therapeutic Mesenchymal Stem/Stromal Cells

Abstract

Mesenchymal stem/stromal cells (MSCs) present a promising tool in cell‐based therapy for treatment of various diseases. Currently, optimization of treatment protocols in clinical studies is complicated by the variations in cell dosing, diverse methods used to deliver MSCs, and the variety of methods used for tracking MSCs in vivo. Most studies use a dose escalation approach, and attempt to correlate efficacy with total cell dose. Optimization could be accelerated through specific understanding of MSC distribution in vivo, long‐term viability, as well as their biological fate. While it is not possible to quantitatively detect MSCs in most targeted organs over long time periods after systemic administration in clinical trials, it is increasingly possible to apply pharmacokinetic modeling to predict their distribution and persistence. This Review outlines current understanding of the in vivo kinetics of exogenously administered MSCs, provides a critical analysis of the methods used for quantitative MSC detection in these studies, and discusses the application of pharmacokinetic modeling to these data. Finally, we provide insights on and perspectives for future development of effective therapeutic strategies using pharmacokinetic modeling to maximize MSC therapy and minimize potential side effects. Stem Cells Translational Medicine 2018;7:78–86

Viral inactivation of human platelet lysate by gamma irradiation preserves its optimal efficiency in the expansion of human bone marrow mesenchymal stromal cells

“…4 Their unique biological features made them a candidate of choice in cell therapy clinical trials, mainly for immunomodulation and regenerative medicine purposes. 1,5 Due to the small occurrence of hMSCs in the BM, 6 a step of cell expansion is necessary prior to cell infusion to the patient 7 and historically implies the use of animal-derived elements, such as fetal bovine serum (FBS), leading notably to immunological concern. 8, 9 Human platelet lysate (hPL), obtained from the lysis of human platelets, is particularly rich in growth factors (GF) and nutritive elements.…”

Dissecting the Pharmacodynamics and Pharmacokinetics of MSCs to Overcome Limitations in Their Clinical Translation

“… 104 Considering their safety, MSCs are introduced into clinical practice for a variety of severe and/or rare pathologic conditions when standard approaches have limitations or are no longer effective. 105 Although this strategy is usual during drug development in clinical translation, it represents a limiting factor for MSC potential that often finds end-stage diseases to be counteracted, relying on unclear PK-PD. Despite the growing applications of MSCs in trials, much still needs to be addressed regarding their biodistribution, especially because clinical success of an MSC-based product should require preclinical research with appropriate PK-PD investigations in early phases of development to better understand MSC functions and increase their efficacy in patients.…”

Myh11+ microvascular mural cells and derived mesenchymal stem cells promote retinal fibrosis

“…Despite the evidence of potentially deleterious mural cell-to-myofibroblast differentiation in vivo, mural cells are commonly isolated and harvested from the stromal vascular fraction (SVF) of tissues, such as adipose and bone marrow, and used as a therapy in treating a panoply of conditions, with applications in promoting wound healing, stimulating bone replacement, diminishing inflammatory disease, and improving erectile dysfunction 14 , 15 . However, the cell fate of these injected cells remains largely unexplored, and at times, the delivered MSCs derived from the SVF are not even found after the treated tissue is harvested for analysis 16 . Our limited knowledge of the in vivo cell fate of exogenous MSCs and other cellular components within the SVF very likely contributed to the disastrous and unexpected blinding of multiple patients following injection of the autologous SVF into the vitreous as a treatment for age-related macular degeneration 17 .…”