Abstract
Mesenchymal stromal cells (MSC) have been proposed as an emerging cell-based therapeutic option for regenerative medicine applications as these cells can promote tissue and organ repair. In particular, MSC have been applied for the treatment of bone fractures. However, the healing capacity of these fractures is often compromised by patient’s age. Therefore, considering the use of autologous MSC, we evaluated the impact of donor age on the osteogenic potential of bone marrow (BM)-derived MSC. MSC from older patients (60 and 80 years old) demonstrated impaired proliferative and osteogenic capacities compared to MSC isolated from younger patients (30 and 45 years old), suggesting that aging potentially changes the quantity and quality of MSC. Moreover, in this study, we investigated the capacity of the microenvironment [i.e., extracellular matrix (ECM)] to rescue the impaired proliferative and osteogenic potential of aged MSC. In this context, we aimed to understand if BM MSC features could be modulated by exposure to an ECM derived from cells obtained from young or old donors. When aged MSC were cultured on decellularized ECM derived from young MSC, their in vitro proliferative and osteogenic capacities were enhanced, which did not happen when cultured on old ECM. Our results suggest that the microenvironment, specifically the ECM, plays a crucial role in the quality (assessed in terms of osteogenic differentiation capacity) and quantity of MSC. Specifically, the aging of ECM is determinant of osteogenic differentiation of MSC. In fact, old MSC maintained on a young ECM produced higher amounts of extracellularly deposited calcium (9.10 ± 0.22 vs. 4.69 ± 1.41 μg.μl–1.10–7 cells for young ECM and old ECM, respectively) and up-regulated the expression of osteogenic gene markers such as Runx2 and OPN. Cell rejuvenation by exposure to a functional ECM might be a valuable clinical strategy to overcome the age-related decline in the osteogenic potential of MSC by recapitulating a younger microenvironment, attenuating the effects of aging on the stem cell niche. Overall, this study provides new insights on the osteogenic potential of MSC during aging and opens new possibilities for developing clinical strategies for elderly patients with limited bone formation capacity who currently lack effective treatments.
Highlights
Mesenchymal stromal cells (MSC) have been described as a cell population of multipotent stem/progenitor cells with the ability to proliferate and differentiate into multiple lineages, including adipogenic, chondrogenic, and osteogenic (Pittenger et al, 1999, 2019)
Cells from both ages exhibited similar spindle shaped morphology (Figure 2B). These results suggest that the proliferative capacity of MSC in vitro decreases with the increase of donor age
Clinical studies have shown that aging is associated with bone loss (Zaim et al, 2012; Corrado et al, 2020) and loss of the osteogenic potential of MSC (Sethe et al, 2006; Stolzing and Scutt, 2006; Baker et al, 2015; Pignolo et al, 2021)
Summary
Mesenchymal stromal cells (MSC) have been described as a cell population of multipotent stem/progenitor cells with the ability to proliferate and differentiate into multiple lineages, including adipogenic, chondrogenic, and osteogenic (Pittenger et al, 1999, 2019). Several studies have supported the potential application of ex vivo expanded MSC, mostly of autologous origin (Rapp et al, 2018), to improve the current clinical practices for repairing large bone defects (Schmitt et al, 2012; Perez et al, 2018). The healing capacity of these fractures is often compromised by patients’ age and comorbidities, including diabetes and osteoporosis (Vester et al, 2014; Huang et al, 2016). In this context, it is important to understand the impact of donor age on the therapeutic potential of MSC, when considering the use of autologous MSC to treat non-healing fractures. The impact on donor age is not restricted to cells themselves and to their microenvironment that is known to affect cell function (Asumda, 2013)
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