• Fibroblasts and MSCs are closely related—often overlapping in morphology, surface markers, and even differentiation potential.
• They may exist along a functional spectrum, with MSCs tending to show more plasticity, and fibroblasts being more specialized for ECM production and wound repair.
• Omics data reveal nuanced differences, though practical distinctions still depend on context, source, and intended use.
• Fibroblasts play key roles in clinical applications, especially in skin repair (e.g., Apligraf®, Dermagraft® for diabetic foot ulcers) and are resurging in novel gene and cell therapies.
• RoosterBio now offers Xeno-Free RoosterVial™-hDF supported by a GMP product pipeline, enabling scalable, standardized fibroblast culture for research and translational use.

RoosterBio has listened to the discussions—even controversy—on differences between fibroblasts and mesenchymal stem/stromal cells (MSCs). Are they even “different” at all? Perhaps they could be personified like the fraternal twin tradesmen of the video game franchise, Mario and Luigi. On casual glances, they appear almost identical to the uninitiated. Both do strenuous jobs to support and repair the complex infrastructure of our architectures or tissues.

On closer inspection, however, this heroic duo displays different dispositions. Like our hero Mario, fibroblasts might be more forward-facing (and getting more publicity?), found neck-deep within tougher spots, and more mission-focused. However, Mario’s sidekick (Luigi) behaves a little more delicately, and has additional abilities such as more dynamic mobility. Perhaps MSCs are Luigi’s cellular analog? These cells can be more labile to external stimuli that can induce them to differentiate, move, or secrete. Yet working together as “siblings,” fibroblasts and MSCs can be an unstoppable team for tissue repair and regenerative medicine applications.

Alike Together Because of Blurred Differences Amongst?

As twin stromal cells, MSCs and fibroblasts share the same broad morphology, and both can originate from mesoderm progenitor cells, or even from ectoderm/neural crest in the head. [1, 2] Denu et al., (2016) provocatively report [3] that fibroblasts and MSCs are “phenotypically indistinguishable,” overlapping in morphology and function so completely that they cannot be conceived of as separate. Despite classic 3T3 cells used as a tissue culture mainstay since 1962, there is no established canon to categorize these as the generic “fibroblasts” known in familiar parlance. Hence, it’s equally impossible to strictly declare any MSC to be a fibroblast.  What then, if standard MSC criteria [4] were applied to diverse fibroblast types? The answer may surprise you.

When representative fibroblast cell populations from breast, dermal (foreskin), and lung were assessed for expression of positive and negative MSC markers, [4] it was observed that, just like MSCs, these cells were positive for CD73, CD90, and CD105 while negative for CD14, CD34, CD45, CD19; and HLA-DR. [3] Further, the fibroblasts could be induced to differentiate into adipocytes, chondrocytes, and osteoblasts—another quintessential feature of MSCs. Intriguingly, these fibroblasts could also exert immunomodulatory activities such as suppression of T cell proliferation and education of macrophage phenotypes; immunomodulation accounts for many of MSCs’ lauded therapeutic effects seen with in vivo experiments.

As expertly reviewed by Lendahl et al. (2022), [5] fibroblasts are a very heterogeneous bunch…like MSCs. As the dominant cell type of connective tissue—found in any cubic centimeter of any human body—fibroblasts adopt characteristics like HOX transcription factor expression profiles that are geographically distinct across each anatomical site. [6] Although MSCs are traditionally known as a plastic-adherent cell that grows out of cultured bone marrow aspirates, [7] MSCs (or “MSC-like”) cells have also been isolated from umbilical cord tissues, adipose tissue, menstrual blood, deciduous teeth, heart, and other sites. So, MSC heterogeneity exists from both within origin tissue sources [8]  and among them [9], as well as from different culture/isolation methods [10] or individual donors. [11]

Because fibroblasts and MSCs span such difference amongst themselves, distinctions between each other are blurred. The wide heterogeneity between individual isolations of MSCs and fibroblasts creates high potential for categorical overlap (see Figure 1, below). Like in Seurat’s painting, A Sunday on La Grande Jatte, there are many stories to be told across the canvas of MSCs and fibroblasts. When contending with the MSC/fibroblast dichotomy, it’s tempting to zero in on a limited field of details like within Seurat’s tiny dots of color, while totally losing track of their context—or even the object of the gaze, itself. One’s gaze meandering across flat scenery ultimately beckons exploration into three dimensions, new views from different angles. Remember, when a biologist recites the mantra “It’s all context,” they’re not being mystical, but simply, real.

Figure 1. A proposed, simplified Venn diagram to illustrate overlap and distinction between fibroblasts and MSCs. Lines may be blurry. Fibroblasts and MSCs both largely originate from embryonic mesoderm, excepting cranial populations that are from neural crest; hence both are solidly “mesenchymal stromal cells.” The formal definition for “MSC” [7, 12] specifies phenotypic, morphological, and surface marker parameters that sometimes overlap with fibroblasts, pericytes, or more multipotent cell types. The term “mesenchymal stem cell” was later critiqued [13] by its own original co-discoverer, the late Dr. Arnold Caplan, [14] who then encouraged adoption of “medicinal signaling cell,” or simply, “MSC.” [15, 16]

Perspective, framing, and context between “twin” cell phenotypes can be gradually absorbed from survey of review articles that touch on this subject directly. [17, 18] These illustrate that the likenesses between MSCs and fibroblasts, while skin-deep, can diverge on account of epigenetic decorations, gene expression levels, and enriched Gene Ontology annotations. In a balance of nature and nurture, a single cell may be unique partly due to specific, dynamic biomechanical stresses [19] and local metabolic flux. [20, 21, 22] Microenvironment niche can drive distinctions for each subtype. A challenging (but fair) question has been raised: if MSCs and fibroblasts can be essentially the same, why even bother with MSCs at all, which are more difficult to isolate and establish than humble dermal fibroblasts? [23, 24] The short answer is that it pays to be empirical in finding cell system that works for you. To understand why, read on…

Differences in Hues, Not Black & White

Let’s briefly entertain the idea that MSCs really are identical to fibroblasts. If so, would it not be implausible to change media recipes for one cell type to differentiate it into its counterpart? In contrast, Lee et al. (2014) [25] used connective tissue growth factor (CTGF) as an induction factor to generate fibroblasts out of MSCs. These primed cells adopted a classic, uniformly spindle-like morphology, synthesized more type I collagen and tenascin-c (Tn-C), and did not robustly differentiate into bone or cartilage as per their untreated parental cells.

In a similar vein, the lab of John Davies (U. Toronto) showed that one variety of MSCs (human umbilical cord perivascular cells; HUCPVCs) could expand along a path of gradually restricted differentiation options from quintipotency to monopotency. [26] Under prolonged non-optimized culture conditions, MSCs can retain their classic markers, yet may lose ability to robustly differentiate into myogenic, bone, fat, or cartilage types, [7] declining into a terminal “generic” phenotype of fibroblast. These and other observations led some to posit that fibroblasts are merely “aged MSCs,” [27] exhibiting less colony-forming ability than their more-multipotent precursors. [28] As diagrammed in the review by Lendahl et al. (2022), [5] such differences might be better imagined along a continuum than as rigidly discrete classes (see Figure 2, below). Plasticity between “MSC-like” and “fibroblast-like” poles is further supported by studies which show that dermal fibroblasts can be reverted, back into MSCs. [29, 30] Thus, MSCs may lie in the intermediate zone between more primitive multipotent cells end-differentiated fibroblast types (e.g., myofibroblasts, fibrogenic cells).

Figure 2. Simplified schematic of the developmental path from embryonic germ layers to MSCs and fibroblasts, based on illustration in review by Lendahl et al. [5] The distinguishing characteristics between MSCs and fibroblasts might be assessed along a spectrum: matters of degree toward differentiation potential, not necessarily rigid classification.

MSCs isolated from different donors and sources will express markers that can inform a spectrum of diverse clinically relevant uses. For example, a phenotype between that varies between pro-angiogenic (and more stem-like) or immunomodulatory (and more differentiated) functions can be predicted via the “CLIP scale,” evinced by expression levels of TSG6, TWIST1, and other parameters. [31, 32]  It is proposed that MSCs in vivo nominally persist in a quiescent, lower-oxygen state until activated by local damage, inflammation or more severe hypoxia. Thereafter, awakened from their niches, [33] MSCs assume roles as “first responders” and hustle toward an injury or lesion, [34] perhaps due to signaling pathways involving HIF-1a, Notch, and SUMO. [35] It could be interesting to learn more of where fibroblast subtypes could be aimed therapeutically via molecular readouts such as the MSC CLIP scale.

Being more numerous and in more constant turnover than prototypical MSCs, fibroblasts tend to populate both loose and dense fibrous architectures surrounding the organs and tissues, secreting massive amounts of extracellular matrix (ECM) in TGF-beta dominated milieu. [36] Their industrial “product line” includes collagen type I, the most abundant protein in humans and mammals, [5] which comprises the main raw material for leather, food gelatin, and many cosmetics and biomedical applications. [37] If so-called “clean meat” and cruelty-free leather industries are to break through into mass consumer opportunities, animal fibroblasts and their industrial-scale culture will no doubt be on the front lines, along with MSCs. [38]

The collective ECM secretory products of fibroblasts are known as the matrisome. Matrisomes are tissue and cell-specialized, each with different morphological and molecular features. Most sublimely, even within the same tissue, different fibroblast populations with unique features can be characterized. [39] Like MSCs, fibroblasts can sometimes go awry in aging and illness. Pathogenic fibroblasts contribute to ~45% of all global deaths via fibrotic diseases, a fact sometimes overshadowed by current pharmaceutical emphasis on cancer and inflammation. [40, 41] Yet, fibroblasts’ very presence in so many kinds of pathology underscores their ubiquitous (yet undercelebrated) positive role in health and homeostasis.

Omics: A Flashlight or a Firehose?

Despite directional distinctions between MSCs and fibroblasts, today’s conventional wisdom considers less about how they appear, or even what they do. Rather, most ask “where are they are found and how are they obtained?” Yet, when confronting a limited set of morphological and phenotypic markers that allude to a bewildering story, some intrepid investigators strive to more deeply penetrate “omics” and/or transcription profile array data. To tell fibroblasts and MSCs apart, they seek novel molecular “fingerprints.” [42, 43, 44, 45, 46, 47, 48]

One universal message from MSC “omics” studies is that promising novel biomarkers do pop up within these individual studies. In a binary comparison between bone marrow MSCs and skin fibroblasts across 9600 genes, [43] a panel of 5 differentially expressed transcripts was plucked from the informatics haystack. In another study, Heo et al. (2016) showed that B4GALNT1 expression is confined to bone marrow, cord blood, placental, and adipose MSCs—and absent in fibroblasts. [42] In yet another example, Haydont et al. (2020) [39] identified a fingerprint of 380 discriminant transcript target levels that clustered into MSC and fibroblast specific groups; these could be distilled into a select signature panel of 42 gene products to distinguish MSCs and fibroblasts. Moreover, Budeus et al. (2023) [49] observed differential expression of various HOX genes for MSCs and fibroblasts, a “HOX code.” It seems that there are indeed differences between MSCs and fibroblasts, but that the characteristics are much more than “skin deep.” However, with coordinated follow-up studies needed to validate stainable surface protein markers, it remains to be seen how soon a practical upgrade of the nomenclature to resolve MSC [12, 50] and fibroblast [51] subtleties can be reached.

Sibling Cells Working Together

We know that MSCs and fibroblasts can be found close together in the anatomy, at the same “scenes of the crime.” [45] Given some of their cross-functionality, the question arises of whether their siblinghood is meaningful in live organisms, not merely theoretical. On this, it’s useful to delve into sophisticated genetic models such as conditional knockouts and knock-ins. An exemplar is from the lab of Dr. Jennifer Davis (U. Washington), where MNBL1 was placed under rheostatic, tamoxifen-responsive control in live mouse cardiac fibroblasts. [52] These elegant studies showed that selectively targeted MNBL1 deletion rendered the fibroblasts more MSC-like, developmentally immature, more prone to self-renewal, and not capable of normal, “healthy” scar formation. In the reciprocal experiment, forced expression of MNBL1 in cardiac fibroblasts caused them to adopt a less proliferative, myofibroblast phenotype, showing mature, post-MI scar stabilization but also maladaptive heart remodeling following the injury.

One possible generalization of Professor Davis’ (and others) work is that MSCs and more-differentiated fibroblasts need to operate in a “goldilocks zone” of exquisitely balanced plasticity, responsive to environmental cues that elicit neither too much “soft” stemness nor “rigid” scarring. Aging could partly occur at the level of epigenetic computation that degrades in the form of gene transcription “noise,” [53] which might ramify toward the balanced proportions of cells needed for healthy tissue repair and turnover. [54, 55] Such investigation also may suggest that, in a cell therapy context, the right cell type might be needed for the right job, at the right time. The clinical aim would be to recapitulate youthful wound healing under monitored spatiotemporal cues. Here, MSCs would infiltrate to the lesion and retain themselves on the heels of innate immune cells and their chemokines, helping to first moderate inflammatory exuberance (and septic shock) and next, resolve the ideal margins of local scarring by incoming fibroblasts. [2, 12, 33, 50, 51]

Fibroblasts to the Rescue – Examples of Fibroblasts in Cell Therapies

In the race to the clinic between MSCs and fibroblasts, “Team Mario” (i.e., the fibroblasts) had a long head start. Although MSCs now account for a larger number of trials, fibroblast-based clinical activity found earlier success in select domains. Not unexpectedly, they proved their mettle with skin tissue and wound healing indications. It began with FDA  approval of the Advanced Tissue Sciences (co-developed with Smith & Nephew) Class III medical device product, TransCyte® (aka Dermagraft-TC), in 1997. [56] Transcyte contained irradiated, non-replicative neonatal fibroblasts as a skin burn covering before autografting. Apligraf®, a skin substitute for ulcers from Organogenesis, embodied a layered application with both live keratinocytes and collagen-embedded fibroblasts, and was approved as a “device” in 1998. [57] Advanced Tissue Sciences was next with Dermagraft®, which contained live, allogeneic neonatal fibroblasts, topically applied via an engineered bioabsorbable polyglactin mesh scaffold onto diabetic foot ulcers; the product was eventually acquired by Organogenesis. [58] Dermagraft also was advanced as a device product. Two fibroblast products in Korea followed in 2007 and (Hyalograft 3D, CHA Bio & Diostech Co) and CureSkin in 2010 (S. Biomedics).

After kicking off its premier LaViv™ (FDA approved in 2011 as a Section 351, autologous fibroblast biologic for cosmetic filling of nasolabial folds), its FibroCell developer (now with Castle Creek BioSciences) switched gears to focus on rare skin diseases. It devised with Intrexon a clinical product (FCX-007) where COL7A1 is expressed via lentivirus in ex vivo manipulated autologous fibroblasts for a gene correction of epidermolysis bullosa (EB). This has reached Phase III trials, currently underway. Today, clinicaltrials.gov lists at least 50 human trials posted where fibroblasts are part of or comprise the main therapeutic intervention. While these have mostly been aimed at topical wounds, ulcers, and bones, some are for dental uses, or even spinal injury repair (NCT03933072) or cancer vaccines (NCT02211027).

For HTS, Fibroblasts Bring Their Own Power-Ups

For obvious but sometimes overlooked reasons, primary fibroblasts punch far above their weight in drug screening/HTS studies. Plentifully sourced primary fibroblasts have normal karyotypes and more pristine stress responses to external insults, and proceed through numerous (but finite) population doublings. Though easy to adapt to 96-well plate formats, they aren’t weeds of cell culture, laden with artifacts, nor are they prone to spontaneous transformation. One example among many is a publication by Mannerström et al. (2017), [59] which compared primary human fibroblasts with mouse 3T3s. Although many test compounds were similar in their IC50 toxicity readout, there were some differences, potentially improving the predictive value of the assay for human-specific exposures.

In another example, Schimmel et al. (2020) [60] aimed a natural 480-compound library at a cell culture model of cardiac fibrosis, a major disease process underlying heart failure. The primary cardiac fibroblasts used in the screen reported readouts of proliferation rate and cell death. Compounds that suppressed proliferation but spared the cells from death were advanced farther as leads, which were then further winnowed by their specificity for fibroblasts and ability to suppress collagen type I secretion. In vivo, the two leads (bufalin and lycorine) were highly effective in restoring cardiac function in relevant mouse models. These and other examples boost Our Friend, the Fibroblast to shine as an early bright star in not just regenerative medicine, but also in classic pharma discovery engines.

MSCs & Fibroblasts, Together Again

“Nothing can hurt us as long as we’re together.”  – Luigi, Super Mario Bros Movie

When mapping out a new cell therapy, a tissue engineering project, or the bioproduction of exosomes or mitochondria, it would be wise to test drive the most suitable cell type for the kind of job you want it to do. Just as Mario and Luigi are each “cross-functional” but have specialties and quirks, there may be subtle differences among various MSC/fibroblast tissue origins and donors. After gathering key analytic data in vitro, it might even turn out that the fibroblast (Mario) is the best fit candidate for your program? Or, perhaps, secretome products via MSCs’ conditioned media could use fibroblasts in HTS for anti-fibrotic lead candidates. Alternatively, surely there must be discoveries waiting to show that MSCs and fibroblasts are best added together (as in a co-culture or layered) for the optimal result.

RoosterBio’s extensive panel of MSC donors to screen across bone marrow, umbilical cord, and adipose tissue origins awaits your exploration, and our analytics expertise stands ready to assist with their characterization to provide fit-for-purpose translational insights. With that in mind, we’ve built our product ecosystem to make such exploration seamless — not only for MSCs but now also for their fibroblast “twin.”

Did you know that RoosterBio’s high-performance RoosterNourish™ hMSC expansion media products have been previously reported to support robust growth of fibroblasts? [61, 62] RoosterNourish is available in multiple, scalable formats for both 2D planar as well as 3D bioreactor cell growth, and for benchtop R&D as well as active GMP clinical studies. Independent validation that RoosterNourish is exceptionally well-suite suited for MSCs’ “twin” cells spurred development of a new catalog product launch. We’re thus thrilled to announce  Xeno-Free RoosterVial™-hDF (Xeno-Free Human Dermal Fibroblasts Derived From Neonatal Foreskin).

Xeno-Free RoosterVial™-hDF paired with RoosterNourish(TM) is the first fully scalable manufacturing platform for clinical and commercial fibroblast production. They are derived from neonatal foreskinmanufactured with cGMP-compatible processes, and capable of generating billions of fibroblasts in less than 10 days.  Hence, these are most ideal for product developers who need consistent, rapid fibroblast expansion for tissue engineering, assay development, or EV production. GMP versions are available upon request for translational or clinical needs.

Whether for primary cell-based assay development, preclinical product testing, tissue engineering research, exosome/EV production (paired with RoosterCollect™-EV platforms), or completely novel experimental concepts, we can hardly wait to see how these hardy cells perform in your own lab. No doubt, we’ll be watching!

 

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