More than 1050 clinical trials are registered at FDA.gov that explore multipotent mesenchymal stromal cells (MSCs) for nearly every clinical application imaginable, including neurodegenerative and cardiac disorders, perianal fistulas, graft-versus-host disease, COVID-19, and cancer. Several companies have or are in the process of commercializing MSC-based therapies. However, most of the clinical-stage MSC therapies have been unable to meet primary efficacy end points. The innate therapeutic functions of MSCs administered to humans are not as robust as demonstrated in preclinical studies, and in general, the translation of cell-based therapy is impaired by a myriad of steps that introduce heterogeneity. In this review, we discuss the major clinical challenges with MSC therapies, the details of these challenges, and the potential bioengineering approaches that leverage the unique biology of MSCs to overcome the challenges and achieve more potent and versatile therapies.

Shattering barriers toward clinically meaningful MSC therapies.

Intravascular Mesenchymal Stromal/Stem Cell Therapy Product Diversification: Time for New Clinical Guidelines.

https://journals.sagepub.com/doi/pdf/10.1177/0963689719837897

The Pros and Cons of Mesenchymal Stem Cell-Based Therapies:

For several decades, multipotent mesenchymal stromal cells (MSCs) have been extensively studied for their therapeutic potential across a wide range of diseases. In the preclinical setting, MSCs demonstrate consistent ability to promote tissue healing, down-regulate excessive inflammation and improve outcomes in animal models. Several proposed mechanisms of action have been posited and demonstrated across an array of in vitro models. However, translation into clinical practice has proven considerably more difficult. A number of prominent well-funded late-phase clinical trial have failed, thus calling out for new efforts to optimize product delivery in the clinical setting. In this review, we discuss novel topics critical to the successful translation of MSCs from pre-clinical to clinical applications. In particular, we focus on the major routes of cell delivery, aspects related to hemocompatibility, and potential safety concerns associated with MSC therapy in the different settings.

/pdf/mesenchymal-stromal-cell-therapeutic-delivery-translational-1wr4s1b7p7.pdf

Mesenchymal Stromal Cell Therapeutic Delivery: Translational Challenges to Clinical Application

Mesenchymal stromal cells: Putative microenvironmental modulators become cell therapy

Genetic disruption of chromatin regulators is frequently found in neurodevelopmental disorders (NDDs). While chromatin regulators are attractive therapeutic targets, studies to determine their implication in the etiology of NDDs are limited, preventing advances in diagnosis and treatment strategies. Here, we uncover pathogenic variants in the chromatin modifier Enhancer of Zeste Homologue 1 (EZH1) as the cause of overlapping recessive and dominant NDDs in 17 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 (K27) methyltransferases of the Polycomb Repressive Complex 2 (PRC2). Unlike the other PRC2 subunits, which are associated with the pathogenesis of human cancers and developmental disorders, the implication of EZH1 in human development and disease is largely unknown. Using cellular models and biochemical studies, we demonstrate that recessive variants cause EZH1 loss of function (LOF), while dominant variants are all missense mutations that modify the catalytic activity of EZH1, thus generating a gain of function (GOF) effect. Consistent with a pathogenic effect, depletion or overexpression of EZH1 perturbs neuronal differentiation in the developing chick embryo neural tube. Furthermore, using human pluripotent stem cell (hPSC) derived neural cultures and forebrain organoids, we show that EZH1 LOF and GOF variants respectively delay and accelerate the schedule of cortical projection neuron generation. Our work identifies EZH1 LOF and GOF variants as the genetic basis of previously undefined NDDs and uncovers an essential role of EZH1 in regulating the timing of neurogenesis.

https://www.medrxiv.org/content/medrxiv/early/2022/08/10/2022.08.09.22278430.full.pdf

Gain and loss of function variants in EZH1 disrupt neurogenesis timing and cause overlapping neurodevelopmental disorders

Objective To investigate the thromboembolism induced by blood-mediated inflammatory reactions against infused cells during the clinical application of stem cells. Methods Two patients with renal transplantation and chronic kidney disease, respectively, experienced thromboembolism after umbilical cord mesenchymal stem cell (UCMSC) infusion. The clinical manifestations and the laboratory test results were collected and analyzed. Results The patients received stem cell infusion through the peripheral veins and presented with a swollen and painful forearm postinfusion. Doppler ultrasound showed venous clots at the proximal end of the puncture site. Urokinase and warfarin were used for thrombolytic therapy. The swelling and pain were relieved and cured. Conclusion Safety concerns are still a primary hurdle for stem cell therapy, and thromboembolism as a critical complication should be prevented appropriately.

Thromboembolism Induced by Umbilical Cord Mesenchymal Stem Cell Infusion: A Report of Two Cases and Literature Review

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Gain and loss of function variants in EZH1 disrupt neurogenesis timing and cause overlapping neurodevelopmental disorders

Thromboembolism Induced by Umbilical Cord Mesenchymal Stem Cell Infusion: A Report of Two Cases and Literature Review