New Bioscience Standing on the Shoulders of Old Mice

Our shrew-like kinfolk last scurried together about 70-90 million years ago, back in the Cretaceous Period when pterosaurs cast menacing shadows on the mist-shrouded ferns below. Fast forward to the year 2025, where humans and mice (and other lab critters, e.g., beagles) share a complicated relationship, especially in life sciences. There’s no denying the incalculable murine sacrifices on our behalf, or the 1000s of indispensable breakthroughs they humbly contributed to biomedical science. However, technology to employ human ex vivo primary cells, engineered tissues, biochips, and organoids is rapidly exceeding a century’s worth of inbred rodent lab colonies. These also leap beyond monolayer cell culture and the classic, 96-well plate format…perhaps a little of the best of both worlds.

We know that mice cells maintain active telomerase, giving rise to long telomeres yet with short lifespans; humans’ telomeres gradually erode across lifespans twenty-fold longer. So, the kinds of cancers we develop tend to be quite different. [1] Mouse metabolism is also much more rapid, and their diverging complement of cytochrome P450 enzymes (CYPs) creates translational gaps. [2] And further, our alphabet soups of cytokines, chemokines, and cellular effectors respond differently to challenges and are proportioned differently. [3, 4] Given that mice and humans are not quite the same, many curious surprises pop up between genomes with only ~85% similarity at the protein coding level and 30-50% similarity across gene regulatory regions. Nevertheless, mice are known to “sing” during courtship and demonstrate play behaviors. (What!? Mice ≠ petri dishes!?) Just like us, they also get stressed out and disheveled. Could emerging technologies offer renewed possibility to “live and let live,” i.e., to enrich our own humanity through deeper understanding and empathy across species?

The Roadmap to Launch a Million Chips

On April 4, 2025, the FDA announced such an opportunity on the coattails of the US Congress FDA Modernization Act 2.0. The overt rationale was, of course, less about Stuart Little and more about streamlining long-sought cures for human unmet medical needs. With the publishing of the Roadmap to Reducing Animal Testing in Preclinical Safety Studies, [5] there is the tacit understanding that these changes will be evolutionary before being hailed as revolutionary. But they aim to strike at the root of a troublesome problem: ~90% of drugs fail on their path through clinical trials, from IND to market. Some even fail later when in broad use, with tragic consequences. [6] This is wasteful and even harmful to patients and developers alike, with development costs loaded into sky-high prices that claw their way out of a compressed market time window prior to the dreaded patent cliff. Thus, if the Roadmap’s “New Approach Methodologies” (NAMs) such as human organoids, organ-on-a-chip (OOC) and microphysiological systems (MPS), and computational in silico models can effectively “evaluate immunogenicity, toxicity, and pharmacodynamics in humans,” it sounds less like a zero-sum game and more like a “win-win” for diverse humans interests, and even the animals they replace.

In parallel with the FDA Roadmap, the National Institute of Standards and Technology (NIST) has recently been busy leading a Working Group Developing Standards for Organ-on-a-Chip Research. [7] Together with engineered tissue and mini-organs, OOCs show vast potential to recapitulate features of human physiology that are germane to drug development and higher throughput screening. Just as we’ve enjoyed common standards for internet transfer protocols (TCP/IP), Bluetooth, WI-FI, electric power transmission, radio spectrum bands, railroad gauges, shipping containers, and highway traffic, isn’t it sensible to roll out reasonable standards for in vitro drug testing platforms so this new industry can best harness its innate creativity? For the FDA’s and NIST’s ambitious goals of predictable, animal-free, and miniaturized preclinical drug development platforms to work, however, there must a reservoir of various primary cells for use as a raw material, fed by an industrialized supply chain. As one review article states, “A model is only as good as the cells it comprises.” [8]

What are organs on chips (OOCs)? [9] OOCs are microfluidic devices containing living human cells arranged in tissue-relevant structures that aim to mimic the function of an organ or organ system under dynamic conditions. They have micro-scale fluidic channels that replicate blood flow or air exchange and layers of human cells from one or more tissue types. They can modulate operator-controlled mechanical cues like shear stress to simulate breathing or muscle contraction. Finally, they enable real-time monitoring of physiological responses (e.g., barrier integrity, electrical signals, molecular readouts). Thus, all organ-on-a-chips are “Labs-on-Chips” (LOCs), but not all LOCs are OOCs. Some OOCs incorporate externally self-assembled mini-organs or “organoids.” Hence, organoids may be components of OOCs, but OOCs are not themselves organoids.

MSCs in the Pole Position

For organ-on-a-chips, it’s hard to beat the versatility of human mesenchymal stromal cells (hMSCs): a scalable, multipotent workhorse capable of populating chips, self-organizing into diverse tissue types, and secreting functional biomolecules in co-cultures. As outlined in recent reviews, [8, 10, 11, 12] MSCs are emerging as important living components of all types OOC biosystems, whether the fluidics are capillary, pressure-driven, centrifugal, electro-kinetic, or acoustic. MSCs help drive and/or report on controlled stimuli with measurable readouts of differentiation, vascularization, cell-cell signaling, motility, and other parameters.  Today, data from these propel innovations in diagnostics, toxicology, and regenerative modeling beyond what traditional animal testing can now achieve.

Despite their promise, organ-on-a-chip systems are not without limitations. It’s still challenging to recreate the complexity of native human tissues in a manner that remains reliable, reproducible, relevant, and transferable across pairs of hands. Robust cellular raw materials to undergird and industrialize OOCs are thus necessary. Although some OOC platforms rely on immortalized lines, these can be as nearly adrift from normal human physiology as non-human cells. On the other hand, primary cells may display donor-to-donor variability and limited population doublings. This is where mesenchymal stromal cells (MSCs) can dovetail into many practical solutions. With their multipotency, immunomodulatory behavior, and broad availability from adult and perinatal tissues, MSCs could serve as both functional building blocks and supportive biosensors within OOC platforms. Some, such as MSCs from umbilical cord, show extended population doubling capacity.

MSC Niches Go Microfluidic: Bone Marrow-on-a-Chip at Georgia Tech to Advance CAR-Ts

One pivotal demonstration of MSC utility in organ-on-a-chip systems came from the Georgia Tech lab of Professor Krish Roy in ~2019 to design a fully human, multi-niche bone marrow-on-a-chip (hBM-on-a-chip). [13, 14] This microfluidic platform recapitulated three key physiological compartments of the marrow: a mineralized endosteal niche built from osteo-differentiated MSCs, a perivascular niche formed by co-cultured MSCs and endothelial cells in a collagen-fibrin matrix, and a central marrow space that hosted hematopoietic stem and progenitor cells (HSPCs). By spatially layering these niches and incorporating real-time imaging in a 96-well format, the device enabled researchers to evaluate not just cell survival and cytokine expression, but also the radioprotective and homeostatic roles of MSC-derived niches. The endosteal layer significantly increased the maintenance of CD34+ HSPCs and reduced radiation-induced apoptosis, demonstrating the unique capacity of MSCs to actively modulate tissue function in response to stress. These findings advanced the concept that MSCs are not just convenient scaffold-fillers. Instead, they are biologically intelligent components ideally suited for complex, tunable microphysiological systems.

Building on this foundational model, Delta Ghoshal, PhD, and colleagues pushed further, adapting the hBM-on-a-chip to model the bone marrow tumor–immune microenvironment in multiple myeloma. [15, 16] Again, using MSCs to engineer osteogenic and perivascular compartments, the team constructed a perfusable marrow-like environment that could sustain primary myeloma plasma cells alongside vasculature and stromal support. This enabled the team to assess the effectiveness of adoptive CAR-T therapies within a fully human, physiologically structured model. The MSCs played a dual role: supporting long-term survival of malignant cells and shaping the cytokine and ECM milieu that influenced CAR-T efficacy and infiltration. This model represents a powerful proof-of-concept for how MSCs can enable immune–tumor interaction studies within organ-on-a-chip systems. In this application space, animal models can fall dramatically short. By leveraging MSCs’ plasticity and stromal signaling, the Roy Lab has effectively boosted them with new power-ups for novel translational cancer immunotherapy research. We proudly note that RoosterBio’s cells and media have been a material constituent of some of this published work.

Rocket Science Meets Regenerative Science: MSCs on the ISS

In one of the most extreme testbeds imaginable, researchers recently deployed human bone marrow–derived MSCs aboard the International Space Station using a lab-on-a-chip (LOC) platform engineered for microgravity. This autonomous, miniaturized bioreactor was built with organ-on-a-chip principles. Cultured MSC “astronauts” from RoosterBio under continuous perfusion and remote monitoring were instrumental to this Axiom-1 Rakia mission. [17] Despite the austere conditions of space, the MSCs not only survived but robustly differentiated into osteoblasts when exposed to amorphous calcium carbonate (ACC), outperforming conventional calcium sources. These findings highlight the resilience and versatility of MSCs as regenerative building blocks and demonstrate how OOC-informed LOC systems can model complex tissue responses even in spaceflight. If these chips can support bone formation in orbit, their application to Earth-based drug development and musculoskeletal disease modeling is surely just as promising. As one of our previous blogs [18] and a legendary crooner once noted, “If I can make it there, I’ll make it anywhere.”

Nuances in the Niche: When MSCs Might Need a Co-Star

Still, as with any emerging solution, MSC integration into organ-on-a-chip systems brings nuances. A recent study by Emily Margolis and colleagues in Professor Andrew Putnam’s lab at U. Michigan compared MSCs to dermal and lung fibroblasts in a microvasculature-on-a-chip model, evaluating their ability to support endothelial network formation and vessel perfusion. [19] While all stromal types facilitated angiogenesis to some degree, lung fibroblasts drove more extensive capillary morphogenesis and perfusion under static conditions. MSCs from RoosterBio, by contrast, were slower to induce network formation and less effective at supporting perfused lumens. Nevertheless, MSCs did excel in localized perivascular support and adopted αSMA-positive, pericyte-like roles over time. This suggests that while MSCs are promising candidates for dynamic remodeling and immune-modulatory functions, their application in OOC vascularization may benefit from co-culture strategies, flow conditioning, or scaffold optimization. [20] In short, MSCs alone may not always be a one-size-fits-all fix. Yet in the right context, they remain one of the most adaptable, human-relevant, and regulatory-aligned cell types to help move OOC technology from concept to clinic. To provide its cell therapy and tissue engineering customers with expanded options, RoosterBio has expanded its catalog of primary cells to include human dermal fibroblasts for its cell and tissue engineering tissue solutions. [20]

Putting MSCs in Their Place: Professor Ozbolat’s AAB to Enable OOC Fidelity

While MSCs are showing increasing promise as functional components of organ-on-a-chip systems, scalable and spatially precise bioassembly remains a major engineering hurdle. A compelling response to this challenge comes from Professor Ibrahim Ozbolat’s group (Penn State U.) to develop aspiration-assisted bioprinting (AAB), a novel bioprinting method for picking and precisely depositing MSC spheroids and other biologics with micron-level accuracy. Using both scaffold-based and scaffold-free approaches, AAB enables the bottom-up fabrication of vascularized, osteogenic, and even heterogeneous tissue constructs. Some of these might be composed of MSCs alone, others co-printed with endothelial cells. [21] The authors specifically highlight organ-on-a-chip systems as a target application for AAB. Why? AAB can control spheroid proximity to perfusion channels and tissue interfaces. This platform effectively transforms MSC spheroids from biologic components into programmable building blocks. This breakthrough may clear a path for reproducible, spatially organized tissue models to address the reproducibility and fidelity needs of newer chip-based platforms. As it turns out, MSCs from RoosterBio could be well integrated with the bioprinter’s operating parameters when applied in this context.

A Revised Ending for the Story of Mice & Men: Build It Human

Organ-on-a-chip systems were first conceived to solve a fundamental problem: how to model human biology more accurately than our furry little friends ever could. The goal has always been to create platforms that reflect living human tissues that are responsive, complex, and predictive to decipher disease and accelerate drug discovery. From tumor–immune modeling to space-based tissue formation and precision bioprinting, diverse case studies highlight MSCs as one of the most flexible and powerful springboards for this mission. They bring not just biological realism, but also scalability and standardization, especially when sourced via RoosterBio’s suite of products and bioprocess solutions geared for end-to-end R&D and clinical translation. Indeed, many of the published systems described here used RoosterBio MSCs and/or RoosterNourish™ media.

Are you thinking of devising an organ-on-a-chip system? If you choose to include MSCs or fibroblasts in the recipe, will your cells rise to the occasion? Perhaps consider RoosterBio hMSCs and/or human dermal fibroblasts in your next chip-based experiment, and help script a happier and life-affirming “sequel” chapter to the story of mice and men.

 

References

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