Paneth Cells and ILC3s Drive Context-Dependent GI Regeneration Following BMT

Specific cellular components of the intestinal niche—such as Paneth cells and type 3 innate lymphoid cells (ILC3s)—play critical, targeted roles in promoting stem cell regeneration and epithelial recovery following bone marrow transplant (BMT), explained Alan Hanash, MD, PhD, adult BMT service, immuno-oncology program at Memorial Sloan Kettering Cancer Center.

These findings, which were presented at the 2026 Joint American Society of Transplantation and Cellular Therapy + European Society for Blood and Marrow Transplantation Basic and Translational Scientific Meeting, help explain several overlapping hypotheses on how the gastrointestinal (GI) tract responds to injury and facilitates regeneration after BMT.¹

What Background Research Set the Stage for This Analysis?

The current research was built upon several years of foundational work examining how the intestinal niche responds to injury and the specific cytokines involved in regeneration, Hanash explained. Investigators’ prior work established a framework in which IL-22 plays a critical role in promoting regeneration and survival of the intestinal stem cell (ISC) compartment following the toxic effects of transplant conditioning. Additional research identified IL-33 as another key cytokine in this process, demonstrating that stem cells respond to damage by increasing IL-33 signaling, which in turn stimulates the niche to elevate epidermal growth factor (EGF) expression and promote tissue-intrinsic regeneration. Previous studies also revealed a dual role for infiltrating T cells, which can support stem cell proliferation through interferon gamma production while simultaneously contributing to tissue damage and inducing stem cell apoptosis.^1-3

Foundational work on stem cell niche biology further informed the current study. Existing research demonstrated that ISCs are located at the base of intestinal crypts, marked by LGR5, where they sit adjacent to Paneth cells, which provide essential growth factors such as Wnt3, EGF, and Notch ligands. Both experimental models and patient data had previously shown that allogeneic transplants reduce Paneth cell frequency and that lower Paneth cell levels are associated with greater graft-versus-host disease (GVHD) severity and an increased risk of steroid-refractory disease. However, earlier work by researchers including Ramesh Shawnee and Clinker’s Group challenged the necessity of Paneth cells, demonstrating that mice could remain healthy even when Paneth cells were replaced or ablated, suggesting their niche function may be redundant in vivo. This apparent conflict directly motivated investigators to take a deeper look at the role of Paneth cells.^1,3,4

Additional background research involving ILCs also shaped the study’s rationale. Prior findings established that ILC3s are the primary producers of IL-22 necessary for tissue regeneration following transplant. Human clinical data further suggested an association between these cells and patient outcomes, showing that higher frequencies of ILCs following transplant are linked to a lower incidence of GVHD. Together, this body of evidence—including foundational niche biology, clinical correlations of cell loss, and conflicting findings surrounding niche redundancy—provided the impetus for investigators to explore the targeted migration of ILC3s and the dispensability of Paneth cells in GVHD.^1,4,5

“So, Paneth cells and their niche function could potentially be essential for learning GVHD severity, but are they really? It's not necessarily that clear,” Hanash said during the presentation. “What [prior data] showed is that if you replace Paneth cells in the [mouse’s] precursors, the mouse is actually okay, the stem cells are okay, and the GI tract is largely okay, so it really seems that those Paneth cells might be important for niche function in vitro.”¹

Do Paneth Cells Play a Critical Role in Epithelial Maintenance During Tissue Damage?

Hanash explained that the role of Paneth cells in epithelial maintenance appears to be context-dependent, meaning they are critical in some forms of tissue injury but are considered dispensable in others. For instance, Paneth cell niche function is not essential during experimental GVHD or allogeneic BMT, even though they produce important growth factors (eg, Wnt3, EGF, and Notch ligands), other secretory lineage cells (including goblet cells and enteroendocrine cells) also generate these factors. During GVHD, despite the loss of Paneth cells, these alternative secretory populations expand and continue providing the niche support necessary for epithelial maintenance. In mouse models, the removal of Paneth cells prior to an allogeneic transplant resulted in what Hanash described as “no difference whatsoever,” in tissue damage severity, systemic illness, or stem cell loss when compared with mice that retained intact Paneth cells.¹

Conversely, Paneth cells were found to play a critical role in regeneration following high-dose radiation injury. Within this specific setting, Paneth cells function as a nonredundant source of EGF. When Paneth cells were ablated prior to exposure to radiation, investigators observed a substantially greater loss of stem cells and an attenuated regenerative response; however, this impaired regeneration could be reversed through treatment with exogenous EGF, which restored both stem cell frequency and crypt regeneration to normal levels.¹

Although Paneth cells provide critical niche functions, these functions are only indispensable in select injury settings, such as radiation-induced damage. During GVHD, the GI system appears to possess sufficient redundancy to preserve epithelial maintenance even in the absence of Paneth cells.¹

What Are the Clinical Implications?

The findings from these studies offer several important clinical implications for improving outcomes in patients undergoing allogeneic hematopoietic cell transplantation, particularly in the management of intestinal toxicity and GVHD. Hanash reported that one major implication stems from the discovery that Paneth cells serve as a nonredundant source of EGF specifically during radiation-induced injury, suggesting that EGF or EGF-mimetic therapies may represent a viable clinical strategy to mitigate GI toxicity caused by conditioning regimens (eg, total body irradiation).¹

These data also challenge previous assumptions about the role of Paneth cells in GVHD pathophysiology. Paneth cell loss may not be the primary driver of GVHD severity, as the intestinal niche appears to possess a compensatory backup system. More specifically, goblet cells and enteroendocrine cells expand and continue producing the growth factors necessary to support epithelial maintenance when Paneth cells are lost, and as a result, therapies targeting Paneth cell niche function alone may be insufficient for treating GVHD. Clinical approaches may instead need to prioritize broader preservation of the secretory lineage compartment or the signaling factors these cells produce.¹

Additional findings highlighted the importance of the ILC3/IL-22 regenerative pathway in tissue recovery after transplant. Investigators identified the targeted migration of ILC3s to intestinal crypts through the CXCL16/CXCR6 pathway as a critical component of regeneration. This observation raises several important clinical considerations, including the potential to preserve or enhance this migration pathway to improve transplant outcomes by promoting tissue repair and reducing posttransplant injury.¹

Furthermore, because higher frequencies of ILCs in human patients following transplant have been associated with a lower incidence of GVHD, monitoring these cells may serve as a predictive biomarker of regenerative capacity. The investigators also noted the existence of a short-lived early window, approximately 3 to 4 days following transplant, during which ILCs infiltrate tissues and promote healing before they may be depleted by T cells. This finding suggests that therapies targeting this regenerative pathway would likely need to be administered very early in the transplant process to maximize efficacy.

Hanash emphasized these findings shift attention toward epithelial-intrinsic and niche-based therapeutic strategies. Rather than relying only on immunosuppression to prevent tissue injury, future clinical approaches may focus on actively promoting crypt regeneration through cytokines such as IL-22 or growth factors such as EGF to preserve intestinal barrier integrity and potentially reduce the systemic complications associated with GVHD.¹

“This migration correlates with the regeneration. If we plot the pathway, you'll get the regeneration, and the amount of damage is severe,” Hanash concluded. “So we wonder, potentially preserving or enhancing this regenerative pathway, could be the definition of transplantation.”¹

REFERENCES

1. Hanash A. Stem Cell Biology: Immune-Mediated Regulation of the Intestinal Stem Cell Compartment After Bone Marrow Transplantation. Presented at: Joint American Society of Transplantation and Cellular Therapy + European Society for Blood and Marrow Transplantation Basic and Translational Scientific Meeting; Philadelphia, Pennsylvania. May 28–29, 2026.

2. Hanash AM, Dudakov JA, Hua G, et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity. 2012;37(2):339-350. doi:10.1016/j.immuni.2012.05.028

3. Calafiore M, Fu YY, Vinci P, et al. A tissue-intrinsic IL-33/EGF circuit promotes epithelial regeneration after intestinal injury. Nat Commun 14, 5411 (2023). doi:10.1038/s41467-023-40993-5

4. Takashima S, Martin ML, Jansen SA, et al. T cell-derived interferon-γ programs stem cell death in immune-mediated intestinal damage. Sci Immunol. 2019;4(42):eaay8556. doi:10.1126/sciimmunol.aay8556

5. Takashima S, Sharma R, Chang W, et al. STAT1 regulates immune-mediated intestinal stem cell proliferation and epithelial regeneration. Nat Commun 16, 138 (2025). doi:10.1038/s41467-024-55227-5