Augmentation of Musculoskeletal Regeneration: Role for Pluripotent Stem Cells

Abstract

The rise in the incidence of musculoskeletal diseases is attributed to an increasing ageing population. The debilitating effects of musculoskeletal diseases, coupled with a lack of effective therapies, contribute to huge financial strains on healthcare systems. The focus of regenerative medicine has shifted to pluripotent stem cells (PSCs), namely, human embryonic stem cells and human-induced PSCs, due to the limited success of adult stem cell-based interventions. PSCs constitute a valuable cell source for musculoskeletal regeneration due to their capacity for unlimited self-renewal, ability to differentiate into all cell lineages of the three germ layers and perceived immunoprivileged characteristics. This review summarizes methods for chondrogenic, osteogenic, myogenic and adipogenic differentiation of PSCs and their potential for therapeutic applications.

Versatility of Induced Pluripotent Stem Cells (iPSCs) for Improving the Knowledge on Musculoskeletal Diseases

“…The use of adult cells presents several challenges, such as variation among donors, dependence of functionality on the donor’s age and health condition, heterogenicity, cell scarcity and the use of invasive techniques to obtain them [ 3 , 31 , 128 ]. Nevertheless, current cell-based therapies have not demonstrated full regeneration of most damaged tissues [ 30 , 31 ], except for cell-based therapy for corneal burns [ 129 ] and the gold standard curative bone marrow transplantation [ 130 ]. Nevertheless, the success of these cell-based therapies drives the development of more advanced, innovative cell therapies such as iPSC-based therapies.…”

“…iPSCs’ capacity for self-renewal without losing their pluripotency allows obtaining high numbers of cells to differentiate into the desired cell type. Protocols for iPSCs differentiation into musculoskeletal tissues follow at least one of these basic strategies [ 30 , 44 , 46 , 50 ]: co-culture with primary cells, derivation using combinations of growth factors or small molecules, differentiation through progenitors (MSCs, osteoblasts or myoblasts) and/or differentiation through embryoid body (EB) formation. In the case of myogenic differentiation, EB formation was proved to be less efficient than for chondrogenesis and osteogenesis [ 30 ].…”

“…Protocols for iPSCs differentiation into musculoskeletal tissues follow at least one of these basic strategies [ 30 , 44 , 46 , 50 ]: co-culture with primary cells, derivation using combinations of growth factors or small molecules, differentiation through progenitors (MSCs, osteoblasts or myoblasts) and/or differentiation through embryoid body (EB) formation. In the case of myogenic differentiation, EB formation was proved to be less efficient than for chondrogenesis and osteogenesis [ 30 ]. Other approaches combined seeding or bioprinting iPSCs on bioactive scaffolds [ 45 , 50 , 131 ] or magnetic cell delivery [ 132 ].…”

“…However, the search for cell sources able to restore integrity of musculoskeletal tissues has proven to be challenging [ 26 , 27 , 28 ]. On one hand, human MSCs are scarce and heterogeneous, have limited differentiation capacity and, as previously mentioned, their proliferation is limited by age [ 16 , 29 , 30 , 31 ]. On the other hand, the use of human embryonic stem cells (ESCs) is associated with ethical issues and the risk of rejection when transplanted is an additional disadvantage of using such cells [ 26 , 27 ].…”

“…Efficient and robust differentiation of iPSCs into tissue-specific cell types is crucial both for disease modeling and for regenerative medicine. Should the reader seek a more detailed explanation about iPSC differentiation protocols, please see the previously published studies on osteogenic [ 3 , 30 , 43 , 44 , 45 ], chondrogenic [ 3 , 27 , 30 , 46 ], nucleus pulposus [ 47 , 48 , 49 ] and/or myogenic [ 3 , 30 , 50 ] differentiation of iPSCs.…”