Department of Oral and Maxillofacial Surgery & Special Dental Care, University Medical Center Utrecht, Utrecht University, Utrecht 3508 GA, The Netherlands.
Regenerative Medicine Center Utrecht, Utrecht 3584 CT, The Netherlands.
Stem Cells Transl Med. 2024 Nov 12;13(11):1086-1100. doi: 10.1093/stcltm/szae063.
Endochondral bone regeneration is a promising approach in regenerative medicine. Callus mimics (CMs) are engineered and remodeled into bone tissue upon implantation. The long-term objective is to fabricate a sustainable off-the-shelf treatment option for patients. Devitalization was introduced to facilitate storage and using allogeneic (donor) cells would further propel the off-the-shelf approach. However, allogeneic CMs for bone regeneration pose a potential antigenicity concern. Here, we explored the impact of devitalization on antigenicity and osteoinductive bone formation when implanting syngeneic or allogeneic CM in a vital or devitalized state. For this, we implanted chondrogenically differentiated rat-derived mesenchymal stromal cells using an allogeneic immunocompetent ectopic rat model. Vital syngeneic CMs demonstrated the highest bone formation, and vital allogeneic CMs showed the lowest bone formation, while both devitalized CMs showed comparable intermediate levels of bone formation. Preceding bone formation, the level of tartrate-resistant acid phosphatase staining at 7 and 14 days was proportional to the level of eventual bone formation. No differences were observed for local innate immune responses at any time point before or after bone formation. In contrast, allogeneic CMs elicit a mild adaptive immune response, which still permits bone formation in an immunocompetent environment, albeit at a reduced rate compared to the autologous living counterpart. Overall, devitalization delays bone formation when autologous CMs are implanted, whereas it accelerates bone formation in allogeneic CMs, highlighting the potential of this approach for achieving off-the-shelf treatment.
软骨内骨再生是再生医学中很有前途的一种方法。在植入后，骨模仿物（Callus mimics，CMs）被设计并重塑为骨组织。长期目标是为患者制造一种可持续的现成治疗选择。去细胞化被引入以方便储存，并且使用同种异体（供体）细胞将进一步推动现成方法。然而，用于骨再生的同种异体 CMs 存在潜在的抗原性问题。在这里，我们研究了在活体内或去细胞化状态下植入同种异体或同种异体细胞时，去细胞化对抗原性和成骨诱导骨形成的影响。为此，我们使用同种异体免疫活性异位大鼠模型植入软骨分化的大鼠来源间充质基质细胞。活体内同基因 CMs 表现出最高的骨形成，而活体内同种异体 CMs 表现出最低的骨形成，而两种去细胞化 CMs 则表现出可比的中间水平的骨形成。在骨形成之前，7 天和 14 天的抗酒石酸酸性磷酸酶染色水平与最终骨形成水平成正比。在骨形成之前或之后的任何时间点，都没有观察到局部固有免疫反应的差异。相比之下，同种异体 CMs 会引发轻微的适应性免疫反应，但在免疫活性环境中仍允许骨形成，尽管与自体活细胞相比，骨形成的速度会降低。总体而言，当植入自体 CMs 时，去细胞化会延迟骨形成，而在同种异体 CMs 中则会加速骨形成，这突显了该方法实现现成治疗的潜力。
