Hurdles to uptake of mesenchymal stem cells and their progenitors in therapeutic products.

Biochemical Journal (2020) 477 3349–3366 https://doi.org/10.1042/BCJ20190382 Review Article Hurdles to uptake of mesenchymal stem cells and their progenitors in therapeutic products Peter G. Childs1,2, Stuart Reid2, Manuel Salmeron-Sanchez1 and Matthew J. Dalby3, * 1 Centre for the Cellular Microenvironment, Division of Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Glasgow, Glasgow G12 8QQ, U.K.; 2Centre for the Cellular Microenvironment, SUPA Department of Biomedical Engineering, University of Strathclyde, Glasgow G1 1QE, U.K.; 3Centre for the Cellular Microenvironment, Institute for Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K. Correspondence: Matthew J. Dalby () Twenty-five years have passed since the first clinical trial utilising mesenchymal stomal/ stem cells (MSCs) in 1995. In this time academic research has grown our understanding of MSC biochemistry and our ability to manipulate these cells in vitro using chemical, biomaterial, and mechanical methods. Research has been emboldened by the promise that MSCs can treat illness and repair damaged tissues through their capacity for immunomodulation and differentiation. Since 1995, 31 therapeutic products containing MSCs and/or progenitors have reached the market with the level of in vitro manipulation varying significantly. In this review, we summarise existing therapeutic products containing MSCs or mesenchymal progenitor cells and examine the challenges faced when developing new therapeutic products. Successful progression to clinical trial, and ultimately market, requires a thorough understanding of these hurdles at the earliest stages of in vitro preclinical development. It is beneficial to understand the health economic benefit for a new product and the reimbursement potential within various healthcare systems. Pre-clinical studies should be selected to demonstrate efficacy and safety for the specific clinical indication in humans, to avoid duplication of effort and minimise animal usage. Early consideration should also be given to manufacturing: how cell manipulation methods will integrate into highly controlled workflows and how they will be scaled up to produce clinically relevant quantities of cells. Finally, we summarise the main regulatory pathways for these clinical products, which can help shape early therapeutic design and testing. Introduction *Matthew Dalby is the recipient of the Biochemical Society’s 2020 Industry and Academic Collaboration Award. Received: 13 May 2020 Revised: 15 August 2020 Accepted: 24 August 2020 Version of Record published: 17 September 2020 As a multipotent cell type, mesenchymal stem (or stromal) cells (MSCs) have been a main source of focus within the field of regenerative medicine [1]. A set of criteria defining this cell population emerged in 2006 from the International Society for Cellular Therapy (ISCT) [2]. The ISCT criteria include: plastic adherence; tri-lineage differentiation potential (osteogenic, chondrogenic, and adipogenic); and a panel of surface markers which are expected (CD105, CD73, and CD90), and not expected (CD45, CD34, CD14, CD11b, CD79a, CD19, and HLA-DR) to be expressed. The ISCT criteria provide a highly beneficial benchmark to standardise studies, even when cell populations are sourced from different tissues. Distinct tissues such as bone marrow, peripheral blood, umbilical cord, and fat have all been shown to contain MSCs [3,4]. Comparative studies have demonstrated that tissue source can impact tri-lineage differentiation potential, along with other cell functions such as proliferation rate and cytokine expression [5,6]. Although cell source is important, there is therapeutic potential for all of these MSC populations, as demonstrated by comparative in vivo studies for osteogenic and chondrogenic repair where both were shown to have regenerative effect [7,8]. Even amongst MSC products, the therapeutic mode of action (MoA) will vary significantly based on clinical indication. From a European regulatory perspective, distinction is made between; somatic cell therapy medicinal products (sCTMPs), which illicit effect through pharmacological, immunological or © 2020 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). 3349 Biochemical Journal (2020) 477 3349–3366 https://doi.org/10.1042/BCJ20190382 metabolic means; and tissue-engineered products (TEPs), which aim to regenerate, repair or replace tissue [9]. In the field of regenerative medicine, MSCs are normally used due to their ability to differentiate into functional progenitor tissue types [1,10]. However, clinical efficacy may be determined by their longevity and ability to engraft. Typically MSCs have a transient and short engraftment duration which can limit their therapeutic efficacy [11]. Methods to increase the persistence of MSCs following implantation are, therefore, a key consideration for specific clinical applications. Biomaterial carriers can provide supportive environments for cells (e.g. injectable hydrogels and protein-based patches) and have shown the ability to retain 50–60% of implanted MSCs versus 10% of cells delivered via saline [12,13]. Pre-treatment of cells (with hypoxia or cytokines) can prepare them for ischemic environments [14] and pharmacological treatment can minimise lineage commitment (e.g. inhibition of the Wnt pathway to maintain MSC multipotency) [15] allowing improved persistence upon implantation. As well as increasing longevity, it has been demonstrated that biomaterials can support MSC viability and drive differentiation via cell–material interactions [16,17]. In terms of immunological MoAs, MSC can interact with immune cells, including T-lymphocytes and dendritic cells. This capacity increases opportunities for allogeneic transplant procedures [18,19] with MSCs acting as a suppressive ‘drug’. The mechanism involves cell-to-cell contact and also the MSC secretome, which includes key factors such as: transforming growth factor beta 1 (TGFb1), hepatocyte growth factor (HGF), C-X-C motif chemokine ligand (CXCL)-10, and CXCL-12 [20,21]. The paracrine impact of MSCs contrasts from the direct replacement of damaged tissue and allows treatment of conditions such as graft-versus-host disease (e.g. as a result of marrow transplantation) [22] or to support islet transplantation [23]. Indeed, such immunomodulatory and anti-inflammatory properties are helping MSCs to find applications in cardiac, hepatic, and even neuronal regenerative approaches [24–29]. As the use of therapeutic MSCs grows it has become important to consider how cell expansion will be achieved, and if a naïve phenotype can be maintained. For some therapeutic purposes, it may be desirable to manipulate MSC phenotype, or to even diffe (...truncated)