Revolutionizing Ovarian Regeneration: The Promise and Perils of Dual-Double Stem Cell Therapy

The field of regenerative medicine has witnessed remarkable advancements, and one of the most promising is the dual-double stem cell therapy combining Mesenchymal Stem Cells (MSCs) and Hematopoietic Stem Cells (HSCs). This innovative approach offers hope for women experiencing ovarian decline, Premature Ovarian Insufficiency (POI), and induced ovarian failure. However, as with any cutting-edge therapy, it comes with its own set of challenges that warrant careful consideration.

MSCs are renowned for their ability to differentiate into various cell types and modulate immune responses. They secrete bioactive molecules that promote angiogenesis, reduce inflammation, and support tissue repair [1,2]. HSCs, on the other hand, are pivotal for haematopoiesis and immune function. When combined, these stem cells create a supportive microenvironment that enhances tissue regeneration [3].

Preclinical studies confirm that MSCs enhance HSC engraftment, improving HSC homing and promoting cell survival without toxicity. However, variability in MSC and HSC sources, doses, and protocols, along with the lack of standardization, limits the clinical translation of these findings, emphasizing the need for further research to optimize therapeutic outcomes [4]. Clinical studies have shown promising results in patients with severe aplastic anemia, primary myelofibrosis, diabetes mellitus, non-malignant hematological disorders, and β-thalassemia [5-9].

POI treated with stem cell therapy has shown restored ovarian function, normalized hormone levels, and even successful pregnancies [10-12]. The synergy between MSCs and HSCs seems to amplify the regenerative potential beyond what each could achieve individually.

Successfully restoring ovarian function has profound implications. Beyond fertility, ovarian health affects overall well-being, including cardiovascular health, bone density, and mental health. By potentially reversing ovarian decline, this therapy could improve the quality of life for many women [13]. Moreover, the approach aligns with the personalized medicine paradigm. Given the variability in stem cell sources and patient-specific factors, treatments can be tailored to individual needs, potentially increasing efficacy and reducing adverse effects [1].

Despite the excitement, it’s crucial to address the therapy’s risks.
A. Immunogenicity and Tumorigenicity: While the use of autologous (patient-derived) non-manipulated (non-expanded) stem cells significantly reduces the risk of immunogenicity and tumorigenicity, these risks are not entirely eliminated [14,12]. Autologous non-expanded cells are less likely to provoke an immune response since they originate from the patient’s own body, and they have a lower risk of forming tumors compared to manipulated or expanded cells.
B. Complex Immune Interactions: The intricate interplay between MSCs and HSCs requires meticulous management. Balancing immune modulation without triggering adverse reactions is a delicate task that necessitates thorough understanding and precise execution [15].
C. Safety of Autologous Non-Expanded Cells: Using autologous non-expanded stem cells minimizes concerns related to immunogenicity and tumorigenicity. However, challenges remain regarding the quantity and quality of cells. Non-expanded cells may be present in insufficient quantities to achieve optimal therapeutic efficacy [10]. Without laboratory expansion and stringent quality control, there might be variability in cell potency, potentially leading to inconsistent therapeutic outcomes [11].

Ethically, the use of stem cells must be carefully regulated to prevent misuse. Ensuring informed consent, understanding longterm effects, and maintaining transparency in clinical trials are imperative to uphold ethical standards [16].

Regulatory frameworks must evolve alongside scientific advancements to ensure patient safety without stifling innovation. Guidelines on the use of autologous non-expanded cells need to be established to address the unique challenges associated with their use [17].

Continued research is essential to fully understand and optimize this therapy. Large-scale clinical trials are needed to establish standardized protocols, determine long-term safety, and identify which patients are most likely to benefit [12].

Collaboration between scientists, clinicians, ethicists, and policymakers will be key in navigating these uncharted waters. Developing comprehensive guidelines will help in maximizing benefits while mitigating risks, particularly those associated with cell quality and therapeutic consistency.

Dual-double stem cell therapy represents a significant leap forward in treating ovarian decline. The combination of MSCs and HSCs harnesses the strengths of both, offering a potent regenerative approach. While the potential benefits are immense, they must be weighed against the risks and ethical considerations.

As we stand on the brink of what could be a transformative treatment for ovarian insufficiency, cautious optimism is warranted. With rigorous research, ethical diligence, and thoughtful regulation, this therapy could herald a new era in reproductive medicine, offering hope to countless women worldwide.

• Ding C, Zhu L, Shen H, Lu J, Zou Q, et al. (2020) The paracrine mechanisms of mesenchymal stem cells in the treatment of chemotherapy-induced ovarian dysfunction. Stem Cell Res Ther 11(1): 507.
• Sobhani A, Akbari M, Nazari H, Soheili ZS, Amidi F, et al. (2018) Comparative study of the effects of bone marrow-derived mesenchymal stem cells and adipose-derived mesenchymal stem cells conditioned medium on the ovarian function of mice with chemotherapy-induced ovarian failure. Cell J 20(2): 272-283.
• Pellicer B, Herraiz S, Garrido N, Pellicer A (2019) In vitro generation of human oocytes from ovarian stem cells. Semin Reprod Med 37(2): 066-076.
• Garrigós MM, Oliveira FA, Nucci MP, Nucci LP, Alves ADH, et al. (2022) How mesenchymal stem cell cotransplantation with hematopoietic stem cells can improve engraftment in animal models. World J Stem Cells 14(8): 658-679.
• Ding L, Han DM, Zheng XL, Yan HM, Xue M, et al. (2021) A study of human leukocyte antigen-haploidentical hematopoietic stem cells transplantation combined with allogenic mesenchymal stem cell infusion for treatment of severe aplastic anemia in pediatric and adolescent patients. Stem Cells Transl Med 10(2): 291-302.
• Madani S, Amanzadi M, Aghayan HR, Setudeh A, Rezaei N, et al. (2022) Investigating the safety and efficacy of hematopoietic and mesenchymal stem cell transplantation for treatment of T1DM: a systematic review and meta-analysis. Syst Rev 11(1): 82.
• Li T, Luo C, Zhang J, Wei L, Sun W, et al. (2021) Efficacy and safety of mesenchymal stem cells co-infusion in allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis. Stem Cell Res Ther 12(1): 246.
• Moghaddam MZ, Mousavi MJ, Ghotloo S (2024) Stem cell-based therapy for systemic lupus erythematosus. J Transl Autoimmun 8: 100241.
• Wang Q, Xu N, Wang Y, Zhang X, Liu L, Zhou H, et al. (2022) Allogeneic stem cell transplantation combined with transfusion of mesenchymal stem cells in primary myelofibrosis: a multicenter retrospective study. Front Oncol 11: 792142.
• Herraiz S, Buigues A, Díaz-García C, Romeu M, Martínez S, et al. (2018) Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril 109(5): 908-918.
• Jiang J, Tang Y, Feng H, Fan J, Duan L, et al. (2020) Bone marrow mesenchymal stem cells therapy for ovarian regeneration in premature ovarian failure rats: A study on long-term follow-up. Front Bioeng Biotechnol 8: 423.
• Ma Y, Liu Z, Zhang X, Jiang Y, Wu J, et al. (2020) Mesenchymal stem cells and their conditioned medium improve oocyte and granulosa cell quality in aged mice. Cell Tissue Res 379(1): 149-160.
• Sun X, Han X, Xu P, Lin J, Yan J (2020) Therapeutic effect of mesenchymal stem cell-derived extracellular vesicles on ovarian function in rats with premature ovarian insufficiency. J Tissue Eng Regen Med 14(12): 1545-1556.
• Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, et al. (2018) Ethical and safety issues of stem cell-based therapy. Int J Med Sci 15(1): 36-45.
• Wang Y, Chen X, Cao W, Shi Y (2014) Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol 15(11): 1009-1016.
• Lysaght T, Campbell AV (2011) Regulating autologous adult stem cells: the FDA steps up. Cell Stem Cell 9(5): 393-396.
• Hyun I, Taylor P, Testa G, Dickens B, Jung KW, et al. (2007) Ethical standards for human-to-animal chimera experiments in stem cell research. Stem Cell Res 1(2):159-163.