Postnatal dermal injuries heal with scars, resulting in major health, psychosocial and economic burdens. Our team has studied the mechanisms of fetal regenerative tissue repair with the ultimate goal to develop anti- fibrotic therapies. In pursuit of this mission and with previous R01 support, our team has (i) found that IL-10 is a key regulator of fetal wound repair and promotes scarless healing, (ii) replicated the fetal scarless phenotype by application of IL-10 on postnatal dermal wounds, (iii) revealed new mechanisms that control extracellular matrix (ECM) remodeling and neovascularization via high molecular weight hyaluronan (HMW-HA) signaling, (iv) demonstrated that HMW-HA drives T lymphocyte-mediated IL-10 expression, (v) recently reported a temporal influx of predominantly CD4+ T lymphocytes in murine skin wounds that correlated with the proliferative and remodeling phases of wound healing, and (vi) obtained evidence that reconstitution of immunity by adoptive transfer of functional CD4+ T lymphocytes in severe combined immune deficient mice significantly reduced inflammation, decreased fibrosis, and healed post-injury dermal wounds with less scarring. While our collective data strongly suggest a concerted HMW-HA-mediated IL-10-dependent crosstalk between fibroblast cells and mobilized T lymphocytes in response to injury, little is known about the identity of IL-10-producing CD4+ T lymphocyte subsets and how they contribute to dermal wound repair outcomes. We hypothesize that: (a) CD4+ lymphocyte subsets differentially regulate postnatal dermal scarring via IL-10- dependent signaling and (b) HA and the hyaladherins transduce signals to drive IL-10 production by CD4+ lymphocytes, which reduces scarring risks. To obtain experimental evidence that supports our hypothesis and provides compelling clues to design effective anti-scar therapies, we propose three specific aims.
In aim 1, we will identify the mechanisms by which IL-10-producing CD4+ T lymphocyte subsets regulate inflammation, ECM formation and angiogenesis to reduce scar formation in vitro and in vivo. In this and subsequent aims, we will use unique 10Bit4 mouse models engineered with a triple reporter system - IL-4 (RFP), Il-10 (CD90.1), and Foxp3 (GFP) - to unambiguously assess the requirement of different T lymphocyte subsets presumed to transduce anti-scar functions.
In aim 2, we will investigate how HA regulates CD4+ lymphocyte production of IL-10 via CD44 signaling, and determine how HA-stabilizing hyaladherins influence this signaling cascade. Finally in aim 3, we will determine if HA-mediated endogenous IL-10 production can direct adult fibroblasts toward a fetal-like regenerative phenotype and if this signaling can influence human scarring phenotypes. Using our gained knowledge, we will then optimize a translational HMW-HA-based hydrogel treatment system to promote stable IL-10 production by CD4+ lymphocytes in dermal wounds and test its effects on scarring outcomes in a preclinical wound healing model. Overall, the proposed aims will reveal new CD4+ lymphocyte physiology in wound healing and lead to a novel translational treatment paradigm to mitigate dermal scarring.

Public Health Relevance

The present research addresses a prevalent healthcare problem of dermal scarring that affects patients worldwide after they suffer an injury. Briefly, we aim to identify the cells, molecular mediators, and mechanisms that are directly responsible for directing a wound to heal with or without scar formation. The knowledge obtained from these studies can be harnessed to develop effective therapeutic means to re-direct the way wounds are repaired and thus prevent the debilitating health, psychosocial, and/or economic burdens associated with scarring.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Garcia, Martha
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Baylor College of Medicine
Schools of Medicine
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Balaji, Swathi; Wang, Xinyi; King, Alice et al. (2017) Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling. FASEB J 31:868-881
Balaji, Swathi; Han, Nate; Moles, Chad et al. (2015) Angiopoietin-1 improves endothelial progenitor cell-dependent neovascularization in diabetic wounds. Surgery 158:846-56
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Balaji, Swathi; King, Alice; Marsh, Emily et al. (2015) The role of interleukin-10 and hyaluronan in murine fetal fibroblast function in vitro: implications for recapitulating fetal regenerative wound healing. PLoS One 10:e0124302