This study is the first randomized, double-blind, placebo control clinical trial with intravenous delivery of HUC-MSCs in the elderly individuals with frailty. With an aim to investigate the efficacy and safety of transplantation of allogeneic HUC-MSCs in aging frailty, our study has revealed findings pertaining to predetermined primary end points. HUC-MSCs have been demonstrated to be safe and feasible in the context of aging related chronic diseases, as evidenced by the data of several randomized controlled clinical trial (18–21). In line with the numbers of previous trials, intravenously infused allogenic HUC-MSCs did not lead to any severe adverse events or complications, indicating the safety profile of this novel therapeutic approach. Furthermore, the HUC-MSCs treatment in this study induced no adverse immune responses among aging frail individuals, indicating the well-tolerance and feasibility of HUC-MSC-based therapy.
Regarding the primary endpoint defined as the physical component of SF-36 quality of life, our data showed notable improvement in the PCS scores of SF-36 within the group subjected to MSC treatment. This improvement was observed starting from one week after MSC transplantation and persisted until the final follow-up assessments. Additionally, the administration of HUC-MSCs have led to a significant amelioration in EQ-VAS exclusively at 2-, 3-, and 6-month follow-up intervals. Furthermore, the mental component of SF-36 quality of life exhibited significantly enhancement within the MSCs group during the 6-month follow-up periods. In contrast, no differences were observed between the two groups in terms of sleep quality, as evaluated through the PSQI at any of the follow-up time points.
The results in this study have suggested that HUC-MSC therapy produced clinically significant improvement in the quality of life and functional performance outcomes. The findings are in line with previous clinical trials that investigated the therapeutic potential of MSCs administration for aging frailty. A phase I clinical trial conducted by Golpanian et al.(22) has investigated the effects of intravenous infusion of allogenic BM-MSCs on the frail elderly individuals and reported the significant improvements in quality of life and 6-minute walk distance as well as the reduction levels of TNF-α. The consecutive phase II study was a randomized, double-blind, placebo controlled clinical trial conducted by Tompkins et al.(18), which has demonstrated the efficacy of allogenic BM-MSCs in improving quality of life in older adults with frailty. Collectively, these studies support the contention that MSCs-based therapy holds considerable promise as a novel approach for ameliorating and preventing the development of aging frailty. As for the physical component of the SF-36 quality of life, set as a primary endpoint, out data showed that a significant improvement in the PCS of SF-36 were observed at month 6 with patients receiving MSCs compared with placebo. For patients subjected to HUC-MSCs treatment, the greater PCS were reported started from one weeks after the procedure and remained until the end of follow-ups. Furthermore, the MSC treatments leaded to a significant amelioration in the health self-evaluation assessed via EQ-VAS exclusively at the 3- and 6-month follow-ups. In addition to the physical component, the mental composite quality of life was noteworthy enhanced in the MSCs-treated group during the 2-, 3-, and 6-month follow-up periods. However, in this study, there was no significant difference in PSQI score the change between two groups, indicating HUC-MSCs did not exert a beneficial effect on ameliorating sleep quality. This finding is consistent with prior research that patients underwent the transplantation of hematopoietic stem cells experiencing significant sleep disturbances (23). It is noteworthy that sleep quality is influenced by various external factors, such as environmental conditions, psychological diseases and lifestyle choices (24), which may impact the response to HUC-MSC infusion in the context of sleep quality. Also, a longer follow-up period may provide a more comprehensive understanding of MSC therapy on sleep quality.
In this study, intravenous administration of MSCs was considered beneficial for the elderly individuals with frailty. We observed the substantial improvements in the physical performance capacity following the administration of HUC-MSCs. In terms of grip strength, the MSCs group exhibited greater enhancement at the 2-, 3- and 6-month follow-up compared to the control group, which indicated enhanced muscle strength in upper arms. This finding aligns with a preclinical study utilizing MSCs infusion (25), as well as two clinical studies reported by Golpanian et al.(22) and Tompkins et al.(18). In addition, the improved performance in TUG tests, assessing the mobility as well as balance ability (26), exhibited continuous improvement in patients treated with HUC-MSCs during each post-treatment visit. This finding suggested an overall enhancement in physical function among MSCs group. Notably, the result indicated an increase in 4MWT performance at the 6-month follow-up in the MSCs group compared to the placebo group. Aging frailty is an aging related condition, accompanied with the declines in physical capacity and exert negative effects on the quality of life (27), the findings of this trial may highlight the effects of HUC-MSCs in ameliorating physical decline associated with aging frailty. However, it is worth noting that there were no significant differences between the two groups in the performance of the FTSST during each follow-up visit. The negative results of FTSST may be attributed to the relatively small sample size of the study population and short duration of follow-up. Consequently, investigations involving larger sample sizes and longer-term follow-up are warranted to elucidate the therapeutic effect of MSC-based therapy on these outcomes among older adults with frailty.
In the present study, we also observed that MSC treatment could lead to the decrease in the levels of TNF-α as well as IL-17 at the 6-month follow-up. However, there were no significant differences in the levels of IL-8 and IFN-γ between the MSCs group and placebo group. Several explanations for our findings warrant consideration. The reduction in the levels of TNF-α and IL-17 following MSC therapy confirm the anti-inflammatory and immunomodulatory properties of HUC-MSCs. As reported by multiple studies, MSCs have been shown to possess anti-inflammatory effects by inhibiting the production of pro-inflammatory cytokines, thereby further attenuating various degenerative and inflammatory disorders, including aging frailty (9, 10, 28). The declines in both TNF-α and IL-17 levels in older adults treated with HUC-MSCs typically support the current evidence that MSCs can alleviate the systemic chronic low-grade inflammation and thus prevent the procession of aging frailty (10, 18, 22). However, there was no significant difference in the levels of IL-8 and IFN-γ between the MSCs and placebo groups in our study. It is well acknowledged that IL-8 and IFN-γ are pro-inflammatory cytokines involved in inflammation and innate immune responses, playing prominent roles in the recruitment, activation and survival of neutrophils at sites of inflammation (29, 30). The findings of this study may be partially attributed to the small sample sizes. Besides, it is possible that MSCs may exert context-specific effects on specific signaling pathways to regulate inflammation (31). Thus, further investigations are still needed to elucidate the specific mechanisms by which MSCs regulate the production and secretion of pro-inflammatory cytokines. Our findings indicated that intravenous administration of MSCs may mitigate the chronic inflammatory state via reducing the levels of TNF-α and Il-17, the potential mechanisms underlying the anti-inflammatory role of MSCs have not been thoroughly elucidated and thus further investigations are still needed.
MSCs have been shown to possess regenerative and differentiation properties that can contribute to the tissue repair process (32, 33). Our data in this study indicated that HUC-MSCs may exert their beneficial effects through enhancing physical performance and suppressing chronic inflammation. Our study also demonstrated that MSC therapy in aging frailty resulted in increased quality of life. In addition to the anti-inflammatory effects, it is conceivable that MSCs are capable of promoting tissue regeneration, muscle strength as well as the overall physical function. The potential mechanisms underlying the improved physical performance and quality of life following administration of HUC-MSCs may be partially attributed to the regenerative capacity of MSCs. The therapeutic benefit of MSC therapy may be derived from the paracrine action of MSCs such as secretion of growth factors and cytokines that are responsible for modulating the cellular microenvironment, promoting tissue repair and regeneration (34).
Of note, the present study has certain limitations. The relatively short duration of follow-up and the specific characteristics of the study population may influence the immune and inflammatory responses. Additionally, the sample size in our study may have limited our ability to detect small differences, especially in immune parameters. Future studies with larger sample sizes and longer follow-up periods are needed to confirm and further explore the anti-inflammatory and immunomodulatory effects of MSC therapy in aging frailty.