# Combined effects of aging and type 2 diabetes on wound healing in a humanized mouse model

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $251,250

## Abstract

Abstract
Aging is a powerful risk factor for the development of chronic, non-healing foot ulcers in people with type 2
diabetes (T2DM). Diabetic foot ulcers in older adults with T2DM have devastating consequences, leading to
increased risks of amputation and all-cause mortality. There is a compelling, unmet need to develop therapies
to treat these non-healing wounds in this population; however, an appropriate animal model for use in the
development of biotherapeutics and stem cell therapies with a high degree of translatability to human disease
does not exist. Therefore, the overall goal of this proposal is to develop an aged-T2DM humanized mouse
model to study the mechanisms by which the combined effects of aging and T2DM dysregulate the human
immune system of T2DM patients during wound healing and to test therapeutics based on these new insights.
To achieve this goal, two Specific Aims are proposed. The purpose of Specific Aim 1 is to develop a humanized
mouse model engrafted with CD34+ hematopoietic stem cells (HSCs) from aged-T2DM human donors to study
wound healing. The hypothesis is that humanized mice engrafted with CD34+ HSCs from older adults with
diabetes faithfully recapitulate the non-healing wound phenotype and skewed polarization of wound-
infiltrating macrophages that has been documented in human T2DM patients. This model is based on our
published and unpublished findings that T2DM and aging impair wound healing by an oxidant stress-
dependent HSC autonomous mechanism. Thus, the aging-T2DM-associated impairment in wound healing will
be conferred by the donor HSCs from aged-T2DM patients. The purpose of Specific Aim 2 is to determine the
effect of ATLAS therapy on wound healing in humanized mice engrafted with aged-T2DM HSCs. The
hypothesis is that ATLAS treatment of HSCs derived from aged T2DM human donors prior to engraftment into
NSG-SGM3 mice reduces HSC oxidant stress and increases nitric oxide bioavailability that restores normal
macrophage number and polarization in wounds. Our results show that in a T2DM murine model of wound
healing ATLAS, a combination of L-arginine, tetrahydrobiopterin, and L-ascorbate, decreases HSC oxidative
stress and increases HSC NO bioavailability that restores normal wound healing. The development of the
proposed humanized mouse model bridges a major gap between murine wound healing models and human
non-healing foot ulcers in older adults with T2DM; thus, the creation of a highly translatable tool to develop
novel biological therapies to treat non-healing wounds in older adults with T2DM fulfills a major unmet need
for these patients. As a consequence of the results of this project, we hope to greatly reduce the suffering from
this devasting problem that disproportionately affects older adults worldwide.

## Key facts

- **NIH application ID:** 10128834
- **Project number:** 1R21AG067376-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Louis Michael Messina
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $251,250
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128834

## Citation

> US National Institutes of Health, RePORTER application 10128834, Combined effects of aging and type 2 diabetes on wound healing in a humanized mouse model (1R21AG067376-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128834. Licensed CC0.

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