Senescence induced cellular reprogramming drives cnidarian whole body regeneration in the absence of stem cells

Cell fate stability is essential for maintaining law and order in complex animals. However, high stability comes at the cost of reduced plasticity and, by extension, poor regenerative ability. This evolutionary trade off has resulted in modern animals being either simple, plastic, and regenerative, or complex, stable, and non regenerative. The mechanisms that mediate these traits remain unknown. We show that signaling from senescent cells can destabilize the differentiated state of neighboring somatic cells, reprogramming them back to stem cells that drive whole body regeneration in the cnidarian Hydractinia symbiolongicarpus. Pharmacological or genetic inhibition of senescence prevented reprogramming and regeneration. Induction of ectopic senescence resulted in supernumerary stem cells. Therefore, senescence signaling may be an ancient mechanism mediating cellular plasticity. Senescence-induced reprogramming has retained high efficiency in morphologically simple, yet highly regenerative, cnidarians but degenerated to a rudimentary state in many bilaterians. This loss may have rendered their cell fates more stable and thereby enabling the evolution of their complexity at the expense of regenerative powers. Understanding the senescence environment that promotes cellular reprogramming could provide a new avenue to enhance regeneration in mammals.

细胞命运稳定性对于维持复杂动物体内的有序稳态至关重要。然而，高稳定性会以可塑性降低为代价，并进而导致再生能力受损。这种演化权衡使得现生动物分为两类：一类结构简单、可塑性强且具备再生能力；另一类结构复杂、细胞命运稳定但丧失再生能力。调控这类特征的潜在机制至今尚未明确。本研究发现，衰老细胞（senescent cells）分泌的信号可使邻近体细胞的分化状态去稳定化，将其重编程为干细胞，进而触发刺胞动物（cnidarian）共生海葵（Hydractinia symbiolongicarpus）的全身再生过程。采用药物或遗传学手段抑制衰老过程，可阻断细胞重编程与再生过程；而诱导异位衰老则会产生多余的干细胞。由此可见，衰老信号或许是介导细胞可塑性的古老机制。衰老诱导的细胞重编程在结构简单但再生能力极强的刺胞动物中仍保持高效，但在多数两侧对称动物中已退化为雏形状态。这种功能丢失或许使得这些动物的细胞命运稳定性提升，进而使其得以演化出复杂结构，但代价是再生能力的丧失。阐明可促进细胞重编程的衰老微环境，有望为提升哺乳动物的再生能力提供全新思路。