Multiplicity of Mesenchymal Stromal Cells: Finding the Right Route to Therapy

Abstract

Over the last decade, the acceleration in the clinical use of mesenchymal stromal cells (MSCs) has been nothing short of spectacular. Perhaps most surprising is how little we know about the “MSC product.” Although MSCs are being delivered to patients at an alarming rate, the regulatory requirements for MSC therapies (for example in terms of quality assurance and quality control) are nowhere near the expectations of traditional pharmaceuticals. That said, the standards that define a chemical compound or purified recombinant protein cannot be applied with the same stringency to a cell-based therapy. Biological processes are dynamic, adaptive and variable. Heterogeneity will always exist or emerge within even the most rigorously sorted clonal cell populations. With MSCs, perhaps more so than any other therapeutic cell, heterogeneity pervades at multiple levels, from the sample source to the single cell. The research and clinical communities collectively need to recognize and take steps to address this troublesome truth, to ensure that the promise of MSC-based therapies is fulfilled.

Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases

“…MSC-EVs exhibit most of the properties of MSCs and fundamental challenges relating to MSC heterogeneity affect biological properties and therapeutic potential of MSC-EVs, as well [103]. Differences in the proliferation rate, potential for multi-lineage differentiation and immunosuppressive properties of MSCs from different sources are well-documented [104]. Furthermore, even when MSCs were obtained from the same tissue of origin, they could have prodigious donor-to-donor variation in expression of membrane markers, transcriptional and proteomic profile [104].…”

“…Differences in the proliferation rate, potential for multi-lineage differentiation and immunosuppressive properties of MSCs from different sources are well-documented [104]. Furthermore, even when MSCs were obtained from the same tissue of origin, they could have prodigious donor-to-donor variation in expression of membrane markers, transcriptional and proteomic profile [104]. Aging also has a negative influence on self-renewal capacity, differentiation and immunosuppressive characteristics of MSCs, attenuating their therapeutic potential [105].…”

Use of Human Umbilical Cord and Its Byproducts in Tissue Regeneration

“…Human umbilical cord can be easily collected after birth and applied fresh, using the newborn's own, to treat tissue defects in autologous procedures (Živković, 1991;Sandler et al, 2004;Álvaro and Edwin, 2017). It can also be processed in order to obtain byproducts that are used in allogenic therapies Živković, 1991;Iftimia-Mander et al, 2013;Caputo et al, 2016;Wilson et al, 2019). Since the 1970s, it has been reported that HUC and its byproducts have great potential in the repair and regeneration of injured tissues.…”

Polysaccharide-Based Systems for Targeted Stem Cell Differentiation and Bone Regeneration

“…Large number of cells are required for identity verification, quality control, and expansion for grafting [156,157]. In addition, cellular heterogeneity and clonality have to be evaluated during scaled-up culturing [158]. It is anticipated that advances in cell sorting, expansion, and cultivation systems such as high-throughput bioreactors of various types [159] and closed adherent cell culture systems [157] will allow to overcome quality issues with time thus ensuring the safe use of MSCs in patients.…”

“…It is anticipated that advances in cell sorting, expansion, and cultivation systems such as high-throughput bioreactors of various types [159] and closed adherent cell culture systems [157] will allow to overcome quality issues with time thus ensuring the safe use of MSCs in patients. This, of course, has to be accompanied by international regulatory framework adjustments for cell-based products manufacturing and use in trials and clinics [158]. Future effort will be aimed at establishing efficient and safe large-scale cell expansion protocols and harmonization of the regulatory issues related to clinical use of MSCs in regenerative medicine procedures such as tissue grafts.…”