Background: Task-specific microscopy datasets are often small, making it difficult to train deep learning models that learn robust features. While self-supervised learning (SSL) has shown promise through pretraining on large, domain-specific datasets, generalizability across datasets with differing staining protocols and channel configurations remains underexplored. We investigated the generalizability of SSL models pretrained on ImageNet-1k and HPA FOV, evaluating their embeddings on OpenCell with and without fine-tuning, two channel-mismatch strategies, and varying fine-tuning data fractions. We additionally analyzed single-cell embeddings on a labeled OpenCell subset. Result: DINO-based ViT backbones pretrained on HPA FOV or ImageNet-1k transfer well to OpenCell even without fine-tuning. Fine-tuning further improved performance to 0.704 $\pm$ 0.027 (17 classes, multi-class labels). At the single-cell level, the HPA single-cell-pretrained model achieved the highest k-nearest neighbor performance across all neighborhood sizes (macro $F_1$ $\geq$ 0.515). Conclusion: SSL methods like DINO, pretrained on large domain-relevant datasets, enable effective use of deep learning features for fine-tuning on small, task-specific microscopy datasets.

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