Challenges and advances in clinical applications of mesenchymal stromal cells

Abstract

Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.

Keywords: Artificial intelligence (AI); COVID-19; Clinical applications; Extracellular vesicles; Heterogeneity; Mesenchymal stromal cells.

Fig.1

Various sources of MSCs used in the registered clinical trials. MSCs isolated from bone marrow are most widely applied in clinical trials, followed by those from umbilical cord and adipose. MSCs from muscles, tooth are also used

Fig. 2

The main challenges in clinical applications of MSCs. During preparation of the MSC products, the main challenges include: (1) heterogeneity of MSCs resulted from donor variations such as the health status, genetics, gender, and age. (2) The varying degree of stability of stemness and differentiation capacities between MSCs isolated from different sources, such as bone marrow, adipose tissue, umbilical cord, or muscles. (3) The varying level of expansion capacities under different culture conditions, including confluence, culture surface, oxygen levels, flasks/bioreactors, passage number, and cell surface modifications. At the state of application, challenges remain due to the influence of (1) the homing or migratory capacity of MSCs under different administration route (local/systemic), injection site, infusion time, and cell carrier materials. (2) The immune compatibility between donors and recipients is the key to reduce the risk of rejection, but is affected by environmental inflammatory molecules which could induce distinct expression of MHC-II in MSCs. (3) The complex effective components released by MSCs depending on the host microenvironment (inflammation status, hypoxia, and ECM), which can result in highly variable factors shaping distinct functions of MSCs

Fig. 3

MSCs exhibit heterogeneity at multiple levels. Heterogeneity of MSCs is determined by factors at multiple levels. (1) Donors at different health status, genetics, gender, and age may result in variations. (2) Tissue from different sources exhibits distinct characteristics, therefore leading to heterogeneity. (3) Cell isolation techniques may lead to distinct purity and sub-populations. (4) Cell culture environment and preservation conditions could affect the expansion and states of MSCs, therefore also affecting the heterogeneity

Fig. 4

Current attempts to improve MSC treatment. To improve the therapeutic efficiency of MSCs treatment, modification was made mainly in the following aspects: (1) genetic modification of MSCs by viral transduction or CRISPR/Cas9 techniques to engineer MSCs with enhanced homing, potency, or expansion capacities; (2) priming MSCs with small molecules, hypoxia, or structural stimulations by biomaterials to improve MSC function, survival, and therapeutic efficacy, thus boosting their therapeutic efficacy; (3) biomaterial strategies to improve the survival and function of MSCs by offering a scaffold for MSCs adherence, including modifications on dimensionality, stiffness, topographical cues, surface chemistry, and microstructure of biomaterials. (4) Utilize the MSCs secretome as a drug delivery platform for treatment