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Review
. 2024 Jul;34(7):479-492.
doi: 10.1038/s41422-024-00971-y. Epub 2024 May 22.

Past, present, and future of cell replacement therapy for parkinson's disease: a novel emphasis on host immune responses

Tae-Yoon Park  1   2 , Jeha Jeon  1   2 , Young Cha  1   2 , Kwang-Soo Kim  3   4   5   6
Affiliations
Review

Past, present, and future of cell replacement therapy for parkinson's disease: a novel emphasis on host immune responses

Tae-Yoon Park et al. Cell Res. 2024 Jul.

Abstract

Parkinson's disease (PD) stands as the second most common neurodegenerative disorder after Alzheimer's disease, and its prevalence continues to rise with the aging global population. Central to the pathophysiology of PD is the specific degeneration of midbrain dopamine neurons (mDANs) in the substantia nigra. Consequently, cell replacement therapy (CRT) has emerged as a promising treatment approach, initially supported by various open-label clinical studies employing fetal ventral mesencephalic (fVM) cells. Despite the initial favorable results, fVM cell therapy has intrinsic and logistical limitations that hinder its transition to a standard treatment for PD. Recent efforts in the field of cell therapy have shifted its focus towards the utilization of human pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, to surmount existing challenges. However, regardless of the transplantable cell sources (e.g., xenogeneic, allogeneic, or autologous), the poor and variable survival of implanted dopamine cells remains a major obstacle. Emerging evidence highlights the pivotal role of host immune responses following transplantation in influencing the survival of implanted mDANs, underscoring an important area for further research. In this comprehensive review, building upon insights derived from previous fVM transplantation studies, we delve into the functional ramifications of host immune responses on the survival and efficacy of grafted dopamine cells. Furthermore, we explore potential strategic approaches to modulate the host immune response, ultimately aiming for optimal outcomes in future clinical applications of CRT for PD.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Dynamic profiles of molecular and cellular changes following needle trauma.
Upon needle injection, the brain experiences physical damage, leading to the rupture of resident cells such as neurons, astrocytes, microglia, and oligodendrocytes. This rupture results from the impact of the needle, causing these cells to burst. Subsequently, the ruptured cells release damage-associated molecular patterns (DAMPs) rapidly, which affect neighboring cells and trigger the production and secretion of cytokines and chemokines due to activation. Among the cells sensing this response, neutrophils are quickly recruited to the damaged site, playing a pivotal role in promptly eliminating the debris. Concurrently, astrocytes and microglia become increasingly activated and migrate toward the damaged area over time. Approximately by the third day, peripheral monocytes infiltrate, and depending on the severity of the brain damage, T and B cells may also infiltrate, engaging in reparative functions. This sequence of inflammatory processes is crucial for the removal of cell debris resulting from needle trauma, facilitating essential steps for the repair and homeostasis of the damaged area. At the same time, however, this event appears to cause substantial damage and death to engrafted mDANs.
Fig. 2
Fig. 2. Three different phases of hPSC-based CRT when mDANs may die.
Schematic representation of the three phases in which mDANs can die. Phase 1 involves the in vitro differentiation of hPSCs into mDA cells, predominantly comprising mDAPs and mDANs, using optimized procedures. Phase 2 encompasses the harvesting and cryopreservation of in vitro differentiated mDA cells, emphasizing the critical steps of cryopreservation, storage, and thawing. In Phase 3, the final in vivo transplantation occurs, consisting of surgical transplantation, the early stage (< 2 weeks), and the late stage (> 2 weeks) of graft establishment. The potential challenges and considerations at each phase, including cell viability, immune responses, and environmental factors, are discussed for a comprehensive understanding of the optimization process in hPSC-based CRT for PD.
Fig. 3
Fig. 3. Strategies targeting adaptive immunity.
In general, allogeneic transplantation using mDA cells derived from hESCs still necessitates immunosuppression, whereas autologous transplantation with mDA cells from hiPSCs is characterized by immune tolerance, eliminating the need for immunosuppressants. An alternative strategy, distinct from utilizing autologous cells, involves the application of HLA-matched hiPSCs to reduce the risk of graft rejection, with ongoing efforts to establish an HLA-matched iPSC bank encompassing a diverse array of donors. Another approach focuses on the development of "universal donor stem cells," incorporating genetic modifications, such as CRISPR/Cas9-mediated knockout of HLA class I and II components, along with lentiviral overexpression of the immune receptor CD47 or HLA-E/G transgene.
Fig. 4
Fig. 4. Strategies targeting innate immunity.
In CRT, the standard procedure involves the injection of cells into the brain using a needle, which induces needle trauma and subsequent secretion of various innate immune response factors, including DAMPs, pro-/anti-inflammatory cytokines, and chemokines. These factors activate surrounding glial cells and lead to the infiltration of peripheral immune cells into the brain, contributing positively to damage repair. However, they also exert a detrimental effect on grafted cells, resulting in severe cell death of mDANs. A potential strategy to enhance the survival of grafted cells involves obtaining autologous TREG cells from the patient, increasing their quantity and functionality, and confirming improved therapeutic effects through co-transplantation into the brain. Additionally, exploring the efficacy of inhibitors, neutralizing antibodies, and encapsulation methods to enhance the survival of grafted cells within the inflammatory microenvironment, combined with the application of TREG technology, represents a promising direction for future advancements in CRT.
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