Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan.
Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan.
Exp Neurol. 2021 Mar;337:113577. doi: 10.1016/j.expneurol.2020.113577. Epub 2020 Dec 24.
Neonatal hypoxic-ischemic encephalopathy (HIE) is a major cause of brain damage in newborns. Although therapeutic hypothermia has been shown to be neuroprotective against neonatal HIE in clinical trials, its effect is not satisfactory. Cell-based therapies have attracted much attention as novel treatments for HIE. Preclinical studies on a variety of human cell transplantation methods have been performed in immunodeficient/immunosuppressed animals, such as severe combined immunodeficient (SCID) mice, which lack functional T and B lymphocytes. The detailed characteristics of neonatal HIE in SCID mice, however, have not been delineated. In preclinical studies, novel therapies for neonatal HIE should be evaluated in combination with hypothermia, which has become a standard treatment for neonatal HIE. However, the effects of hypothermia in SCID mice have not been delineated. In the present study, we compared neonatal hypoxic-ischemic (HI) brain damage in SCID mice and wild-type mice treated with or without hypothermia. Male and female mouse pups were subjected to HI insult induced by unilateral common carotid artery ligation combined with systemic hypoxia on postnatal day 12. In the first 4 h after HI insult, body temperature was maintained at 36 °C for the normothermia groups or 32 °C for the hypothermia groups. The severity of brain damage in SCID mice did not differ from that in wild-type mice based on most evaluations, i.e., cerebral blood flow, hemiparesis, muscle strength, spontaneous activity, cerebral hemispheric volume, neuropathological injury, and serum cytokine levels, although spleen weight, brain weight, leukocyte counts and the levels of some cytokines in the peripheral blood were different between genotypes. The effects of hypothermia in SCID mice were comparable to those in wild-type mice based on most evaluations. Taken together, these findings indicate that SCID mice can be used as an appropriate preclinical model for cell therapies for neonatal HIE.
新生儿缺氧缺血性脑病（HIE）是新生儿脑损伤的主要原因。虽然临床试验表明，治疗性低温对新生儿 HIE 具有神经保护作用，但效果并不理想。细胞疗法作为 HIE 的新疗法引起了广泛关注。已经在免疫缺陷/免疫抑制动物（如严重联合免疫缺陷（SCID）小鼠）中进行了各种人类细胞移植方法的临床前研究，这些动物缺乏功能性 T 和 B 淋巴细胞。然而，SCID 小鼠中新生儿 HIE 的详细特征尚未描述。在临床前研究中，新型新生儿 HIE 疗法应与低温治疗相结合进行评估，低温治疗已成为新生儿 HIE 的标准治疗方法。然而，SCID 小鼠中低温治疗的效果尚未描述。在本研究中，我们比较了 SCID 小鼠和野生型小鼠在接受或不接受低温治疗的情况下，新生儿缺氧缺血（HI）脑损伤的情况。雄性和雌性小鼠幼崽在出生后第 12 天接受单侧颈总动脉结扎联合全身缺氧诱导的 HI 损伤。在 HI 损伤后的头 4 小时内，将体温维持在 36°C（常温组）或 32°C（低温组）。基于大多数评估，SCID 小鼠的脑损伤严重程度与野生型小鼠没有差异，即大脑血流、偏瘫、肌肉力量、自发活动、大脑半球体积、神经病理学损伤和血清细胞因子水平，尽管脾重、脑重、白细胞计数和外周血中某些细胞因子的水平在基因型之间存在差异。基于大多数评估，低温对 SCID 小鼠的影响与对野生型小鼠的影响相当。综上所述，这些发现表明 SCID 小鼠可作为新生儿 HIE 细胞治疗的合适临床前模型。
