Hidden Treasure in Shells: Bone Marrow-like Hematopoietic Stem Cell Niches Found in Invertebrate Skeletons

On June 25, 2025, our research group published a groundbreaking study in Science Advances titled “Widespread presence of bone marrow-like hematopoietic stem cell niches in invertebrate skeletons”. This study marks the first global discovery of hematopoietic stem cell (HSC) niches within invertebrate skeletons—overturning the long-held belief that skeletal hematopoiesis is unique to vertebrates, offering a novel evolutionary perspective on stem cell biology.

The Cambrian Explosion stands as one of the most significant innovations in Earth’s evolutionary history. Occurring approximately 540 million years ago, this brief window of just 20 million years witnessed the rapid emergence of nearly all major animal phyla, establishing the foundational blueprint for today’s biodiversity. No new phyla have emerged in the 500 million years since, making it an "unprecedented" and "unique" major event in the history of life evolution on Earth. A defining feature of the Cambrian Explosion was the sudden emergence of mineralized skeletons in organisms that were previously soft-bodied. Yet, the evolutionary forces that drove this dramatic shift remain one of the great unsolved mysteries of biology, often referred to as a “great enigma” in the history of life's evolution.

Figure 1. Hematopoietic skeletons in vertebrates versus exoskeletons in invertebrates.

Traditionally, invertebrate exoskeletons have been regarded as inert mineral shells—essentially lifeless "stones". In contrast, vertebrate skeletons are living organs. Their internal bone marrow plays vital roles in lifelong blood formation and immune regulation, making it a central hub of vertebrate physiology. For decades, skeletal hematopoiesis has been considered a hallmark innovation unique to vertebrates—believed as an evolutionary strategy for the transition from aquatic to terrestrial environments. This concept has been established as a canonical principle in biological sciences, often featured in textbooks as a paradigmatic case of evolutionary advancement in animal organisms. In stark contrast, hematopoietic organs in most invertebrate groups remain poorly characterized. Investigations into their hematopoietic systems have historically been confined to soft tissue examinations, resulting in neither the identification of conserved hematopoietic sites nor clear understanding of hematopoietic stem cell origins. This fundamental knowledge gap has led to prolonged stagnation in hematopoietic research across the majority of invertebrate taxa.

Mollusks (commonly referred to as shellfish), constitute the largest marine animal phylum and represent one of the earliest mineralized skeletal systems originating in the early Cambrian Period. Previous studies have shown that molluscan shells possess extraordinary biological characteristics: the ability to preserve ancient DNA for up to 100,000 years (4); remarkable biocompatibility, as evidenced by their use in Mayan dental implants (5); and, the unexpected ability to support vertebrate stem cell viability when used as culture substrates (6, 7). These phenomena bear striking similarities to vertebrate skeletons, yet have always been difficult to explain within the framework of traditional understanding. This raises key scientific questions: Could shells harbor life secrets yet to be discovered? Are shells truly the lifeless "stones" that they are commonly perceived to be? What biological mechanisms lie behind these astonishing phenomena?

The key breakthrough in solving this mystery originated from an unexpected experimental "accident": While processing fresh shells using standard molluscan tissue nucleic acid extraction protocols, the research team serendipitously detected abundant biologically active RNA molecules， revealing the presence of numerous living cells within shells and challenging their conventional classification as "lifeless stone." Confronted with the significant technical challenges of studying hematopoietic stem cell function within hard, opaque shells, the team successfully established a stem cell research system applicable to the exoskeletons of invertebrates after years of intensive effort. Through a combination of multi-omics genetic analysis, in vitro cell culture and induced differentiation, in vivo animal cell tracking, and functional verification, we systematically provided evidence revealing the presence of hematopoietic stem cell niches within shells. The following original discoveries were made:

1. High Abundance of Hematopoietic Stem Cells: Compared to the very low proportion of hematopoietic stem cells or precursor cells in the bone marrow of higher vertebrates (usually <10%), the proportion of hematopoietic stem cells in shells is as high as 40%-60%. Currently, there are still many technical limitations and challenges in human hematopoietic stem cell culture and transplantation. A deeper understanding of the unique high-proportion stem cell maintenance mechanisms in mollusks could provide important insights for stem cell research or therapeutic strategies in regenerative medicine.

2. Ancient Homology of the Hematopoietic Lineage: The hematopoietic lineage in shells exhibits many biological features similar to those in vertebrates. At the omics level, hematopoietic stem cells in shells show low genomic mutation rates, high non-CpG methylation, and specific expression of vertebrate hematopoietic stem cell marker genes. At the stem cell microenvironment level, there is a population of niche-supporting cells corresponding to hematopoietic stem cells in the shells (such as mesenchymal stem cells, macrophages, etc.). From the perspective of developmental origin and biological function, the hematopoietic stem cells in shells show differentiation pathways and systemic blood supply functions similar to vertebrate hematopoietic stem cells. These findings break the traditional view that vertebrate skeletal hematopoiesis is "higher evolution," providing important references for understanding the origin and evolution of animal hematopoietic lineages.

3. Dual Potential for "Hematopoiesis and Mineralization": It was discovered that mollusk hematopoietic stem cells not only have hematopoietic functions but also possess biological mineralization capabilities. Combining recent research on vertebrates, which have dual potential for hematopoietic and osteogenic differentiation in bone-forming regions, it suggests that animal ancestors might have already possessed deep evolutionary links between hematopoiesis and mineralization. These findings not only challenge the traditional view of the mantle as the only mineralized tissue in shells but also provide a new perspective on the functional evolution of hematopoietic systems in the animal kingdom.

4. Conservation of Skeletal Hematopoiesis Across Species: It was found that major animal groups (such as mollusks, crustaceans, echinoderms, and bony fish) with mineralized skeletons all have potential hematopoietic stem cell niches, revealing the core regulatory gene set of hematopoietic stem cells in animal ancestors. A new theoretical concept was proposed: "The significant evolutionary innovation of skeletal stem cell niches may serve as one of the driving forces for the Cambrian Explosion," suggesting that the skeletal system provided a unique ecological niche for hematopoietic stem cells (such as low-oxygen environments favorable for maintaining stemness, while hard shells offer effective radiation protection). This evolutionary advantage was particularly important for coping with environmental changes during the Cambrian period, such as the dramatic increase in atmospheric oxygen and enhanced ultraviolet radiation (9, 10), which could have played a crucial role in the Cambrian explosion of mineralized skeletal animals.

Figure 2. Discovery and Functional Profiling of Hematopoietic Stem Cell Niches in Scallop.

Figure 3. Widespread and potentially deep evolutionary origins of animal skeletal HSC niches.

The original discovery of "the widespread presence of hematopoietic stem cell niches in invertebrate skeletons" marks the first-ever identification of universally conserved stem cell niches across the animal kingdom, representing a significant breakthrough in the field of life sciences. This discovery overturns the traditional view that skeletal hematopoiesis is a unique evolutionary innovation exclusive to vertebrates, and it answers the long-standing academic mystery regarding the origin of hematopoietic stem cells in invertebrates. This groundbreaking finding not only offers a fresh perspective on the origin and evolution of animal hematopoietic systems but also opens up new directions and paradigms for stem cell research in marine organisms.

Based on these discoveries, the team has recently launched the "DeepShell Project," aimed at systematically exploring the evolutionary history of animal skeletal hematopoietic systems from a pan-evolutionary perspective. The goal is to reshape our understanding of hematopoiesis in invertebrates and provide a new theoretical framework for understanding the macroevolution of animal hematopoiesis and mineralized skeletons.

Full paper link: https://www.science.org/doi/10.1126/sciadv.adw0958

Reference:

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